Papers: 21 Jan 2023 - 3 Feb 2023

Cross-talk between peripheral neurons and immune cells is important in pain sensation. We identified Snx25 as a pain-modulating gene in a transgenic mouse line with reduced pain sensitivity. Conditional deletion of Snx25 in monocytes and macrophages, but not in peripheral sensory neurons, in mice (Snx25 mice) reduced pain responses in both normal and neuropathic conditions. Bone marrow transplantation using Snx25 and wild-type mice indicated that macrophages modulated pain sensitivity. Expression of sorting nexin (SNX)25 in dermal macrophages enhanced expression of the neurotrophic factor NGF through the inhibition of ubiquitin-mediated degradation of Nrf2, a transcription factor that activates transcription of Ngf. As such, dermal macrophages set the threshold for pain sensitivity through the production and secretion of NGF into the dermis, and they may cooperate with dorsal root ganglion macrophages in pain perception.

Poor sleep is associated with the risk of developing chronic pain, but how sleep contributes to pain chronicity remains unclear. Here we show that following peripheral nerve injury, cholinergic neurons in the anterior nucleus basalis (aNB) of the basal forebrain are increasingly active during nonrapid eye movement (NREM) sleep in a mouse model of neuropathic pain. These neurons directly activate vasoactive intestinal polypeptide-expressing interneurons in the primary somatosensory cortex (S1), causing disinhibition of pyramidal neurons and allodynia. The hyperactivity of aNB neurons is caused by the increased inputs from the parabrachial nucleus (PB) driven by the injured peripheral afferents. Inhibition of this pathway during NREM sleep, but not wakefulness, corrects neuronal hyperactivation and alleviates pain. Our results reveal that the PB-aNB-S1 pathway during sleep is critical for the generation and maintenance of chronic pain. Inhibiting this pathway during the sleep phase could be important for treating neuropathic pain.

Microglia are important mediators of neuroinflammation, which underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. Here, we investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuates Ca signaling and the production of inflammatory cytokines by proalgesic agonists. Conditional deletion of Orai1 attenuated microglial proliferation in the dorsal horn, spinal cytokine levels, and potentiation of excitatory neurotransmission following peripheral nerve injury. These cellular effects were accompanied by mitigation of pain hyperalgesia in microglial Orai1 knockout mice. A small-molecule Orai1 inhibitor, CM4620, similarly mitigated allodynia in male mice. Unexpectedly, these protective effects were not seen in female mice, revealing sexual dimorphism in Orai1 regulation of microglial reactivity and hyperalgesia. Together, these findings indicate that Orai1 channels are key regulators of the sexually dimorphic role of microglia for the neuroinflammation that underlies neuropathic pain.

Microglia, resident macrophages of the central nervous system (CNS), are essential to brain development, homeostasis, and disease. Microglial activation and proliferation are hallmarks of many CNS diseases including neuropathic pain. However, molecular mechanisms that govern the spinal neuro-immune axis in the setting of neuropathic pain remain incompletely understood. Here we show that genetic ablation or pharmacological blockade of transient receptor potential vanilloid type 4 (TRPV4) markedly attenuated neuropathic pain-like behaviors in a mouse model of spared nerve injury. Mechanistically, microglia-expressed TRPV4 mediated microglial activation and proliferation and promoted functional and structural plasticity of excitatory spinal neurons through releasing lipocalin-2. Our results suggest that microglial TRPV4 channels reside at the center of the neuro-immune axis in the spinal cord that transforms peripheral nerve injury into central sensitization and neuropathic pain, thereby identifying TRPV4 as a promising new target for the treatment of chronic pain.

Sensory neurons of the dorsal root ganglion (DRG) are critical for maintaining tissue homeostasis by sensing and initiating responses to stimuli. While most preclinical studies of DRGs are conducted in rodents, much less is known about the mechanisms of sensory perception in primates. We generated a transcriptome atlas of mouse, guinea pig, cynomolgus monkey, and human DRGs by implementing a common laboratory workflow and multiple data-integration approaches to generate high-resolution cross-species mappings of sensory neuron subtypes. Using our atlas, we identified conserved core modules highlighting subtype-specific biological processes related to inflammatory response. We also identified divergent expression of key genes involved in DRG function, suggesting species-specific adaptations specifically in nociceptors that likely point to divergent function of nociceptors. Among these, we validated that TAFA4, a member of the druggable genome, was expressed in distinct populations of DRG neurons across species, highlighting species-specific programs that are critical for therapeutic development.

Personalised management of neuropathic pain is an unmet clinical need due to heterogeneity of the underlying aetiologies, incompletely understood pathophysiological mechanisms, and limited efficacy of existing treatments. Recent studies on microRNA in pain preclinical models have begun to yield insights into pain-related mechanisms, identifying nociception-related species differences and pinpointing potential drug candidates. With the aim of bridging the translational gap towards the clinic, we generated a human pain-related integrative miRNA and mRNA molecular profile of the epidermis, the tissue hosting small nerve fibres, in a deeply phenotyped cohort of patients with sodium channel-related painful neuropathy not responding to currently available therapies. We identified four miRNAs strongly discriminating patients from healthy individuals, confirming their effect on differentially expressed gene-targets driving peripheral sensory transduction, transmission, modulation, and post-transcriptional modifications, with strong effects on gene targets including NEDD4. We identified a complex epidermal miRNA-mRNA network based on tissue-specific experimental data suggesting a cross-talk between epidermal cells and axons in neuropathy pain. Using immunofluorescence assay and confocal microscopy, we observed that Nav1.7 signal intensity in keratinocytes strongly inversely correlated with NEDD4 expression that was downregulated by miR-30 family, suggesting post-transcriptional fine tuning of pain-related protein expression. Our targeted molecular profiling advances the understanding of specific neuropathic pain fine signatures and may accelerate process towards personalised medicine in patients with neuropathic pain.

Migraine is one of more than 200 headache disorders but stands out among these as a major cause of population ill health. In migraine epidemiology, the key variable is prevalence, but, from the perspective of public health, prevalence is uninformative without burden estimates. Here, we discuss how migraine epidemiology, from a quite recent start, has evolved into the respectable though imperfect science of today, but with the legacy that much of the large corpus of older literature is of questionable reliability. Newer studies have benefited from a universally accepted definition of migraine, while methodological developments have broadened the scope of migraine caseness, and published guidelines address important methodological issues. In the light of these developments, we question the apparent increase in migraine prevalence over time, offering explanations as to why this may be illusory. We suggest that the current best estimates are that global migraine prevalence is 14-15%, and that migraine accounts for 4.9% of global population ill health quantified in years lived with disability (YLDs). These evaluations are probably under-quantified rather than over-quantified, and YLDs are not a comprehensive measure of migraine-attributed burden. Despite these uncertainties, such high estimates of population ill health have clear implications for health policy.

To provide a comprehensive overview of the efficacy, safety, and tolerability of antidepressants for pain according to condition.

Chronic pain is one of the most significant medical problems throughout the world. Recent evidence has confirmed the hippocampus as an active modulator of pain chronicity, but the underlying mechanisms remain unclear. Using in vivo electrophysiology, we identify a neural ensemble in the ventral hippocampal CA1 (vCA1) that shows inhibitory responses to noxious but not innocuous stimuli. Following peripheral inflammation, this ensemble becomes responsive to innocuous stimuli, representing hypersensitivity. Mimicking the inhibition of vCA1 neurons using chemogenetics induces chronic pain-like behaviors in naive mice, whereas activating vCA1 neurons in mice with peripheral inflammation results in a reduction of pain-related behaviors. Pathway-specific manipulation of vCA1 projections to basolateral amygdala (BLA) and infralimbic cortex (IL) shows that these pathways are differentially involved in pain modulation at different temporal stages of chronic inflammatory pain. These results confirm a crucial role of the vCA1 and its circuits in modulating the development of chronic pain.

Administration of a nitric oxide (NO) donor triggers migraine attacks but mechanisms by which this occurs are unknown. Reactive nitroxidative species, including NO and peroxynitrite (PN), have been implicated in nociceptive sensitization and neutralizing PN is anti-nociceptive. We determined whether PN contributes to nociceptive responses in two distinct models of migraine headache. Female and male mice were subjected to three consecutive days of restraint stress or to dural stimulation with the pro-inflammatory cytokine interleukin-6. Following resolution of the initial post-stimulus behavioral responses, animals were tested for hyperalgesic priming using a normally non-noxious dose of the NO donor sodium nitroprusside (SNP) or dural pH 7.0, respectively. We measured periorbital von Frey and grimace responses in both models and measured stress-induced changes in 3-nitrotyrosine (3-NT) expression (a marker for PN activity) and trigeminal ganglia (TG) mitochondrial function. Additionally, we recorded TG neuronal activity in response to the PN generator SIN-1. We then tested the effects of the PN decomposition catalysts, FeTMPyP and FeTPPS, or the PN scavenger MnTBAP against these behavioral, molecular, and neuronal changes. Neutralizing PN attenuated stress-induced periorbital hypersensitivity and priming to SNP, with no effect on priming to dural pH 7.0. These compounds also prevented stress-induced increases in 3-NT expression in both the TG and dura mater and attenuated TG neuronal hyperexcitability caused by SIN-1. Surprisingly, FeTMPyP attenuated changes in TG mitochondrial function caused by SNP in stressed males only. Together, these data strongly implicate PN in migraine mechanisms and highlight the therapeutic potential of targeting PN.Among the most reliable experimental triggers of migraine are nitric oxide donors. Mechanisms by which nitric oxide triggers attacks are unclear but may be due to reactive nitroxidative species such as peroxynitrite. Utilizing mouse models of migraine headache, we show that peroxynitrite-modulating compounds attenuate behavioral, neuronal, and molecular changes caused by repeated stress and nitric oxide donors (two of the most common triggers of migraine in humans). Additionally, our results show a sex-specific regulation of mitochondrial function by peroxynitrite following stress, providing novel insight into the ways in which peroxynitrite may contribute to migraine-related mechanisms. Critically, our data underscore the potential in targeting peroxynitrite formation as a novel therapeutic for the treatment of migraine headache.

Medication overuse headache (MOH) is a secondary headache disorder attributed to overuse of acute headache medications by a person with an underlying headache disorder, usually migraine or tension-type headache. MOH is common among individuals with 15 or more headache days per month. Although MOH is associated with substantial disability and reductions in quality of life, this condition is often under-recognized. As MOH is both preventable and treatable, it warrants greater attention and awareness. The diagnosis of MOH is based on the history and an unremarkable neurological examination, and is made according to the diagnostic criteria of the International Classification of Headache Disorders third edition (ICHD-3). Pathophysiological mechanisms of MOH include altered descending pain modulation, central sensitization and biobehavioural factors. Treatment of MOH includes the use of headache preventive therapies, but essential to success is eliminating the cause, by reducing the frequency of use of acute headache medication, and perhaps withdrawing the overused medication altogether. Appropriate treatment is usually highly effective, leading to reduced headache burden and acute medication consumption.

Induced pluripotent stem cells (iPSC) have enabled the generation of various difficult to access cell types such as human nociceptors. A key challenge associated with human iPSC-derived nociceptors (hiPSCdN) is their prolonged functional maturation. While numerous studies have addressed the expression of classic neuronal markers and ion channels in hiPSCdN, the temporal development of key signaling cascades regulating nociceptor activity has remained largely unexplored.Here we used an immunocytochemical high content imaging approach alongside electrophysiological staging to assess metabotropic and ionotropic signaling of large scale-generated hiPSCdNs across 70 days of in vitro differentiation. During this time period the resting membrane potential became more hyperpolarized, while rheobase, action potential peak amplitude and membrane capacitance increased. After 70 days hiPSCdNs exhibited robust physiological responses induced by GABA, pH-shift, ATP and capsaicin. Direct activation of protein kinase A type II (PKA-II) via adenylyl cyclase stimulation with forskolin resulted in PKA-II activation at all time-points. Depolarization-induced activation of PKA-II emerged after 35 days of differentiation. However, effective inhibition of forskolin-induced PKA-II activation by opioid receptor agonists required 70 days of in vitro differentiation.Our results identify a pronounced time difference between early expression of functionally important ion channels and emergence of regulatory metabotropic sensitizing and desensitizing signaling only at advanced stages of in vitro cultivation, suggesting an independent regulation of ionotropic and metabotropic signaling. These data are relevant for devising future studies into the development and regulation of human nociceptor function and for defining time windows suitable hiPSCdN-based drug discovery.

Intervertebral disc degeneration (IDD) has been reported to be a major cause of low back pain. Interleukin (IL)-37 is an anti-inflammatory cytokine of the interleukin-1 family, which exerts salutary physiological effects. In this study, we assessed the protective effect of IL-37 on IDD progression and its underlying mechanisms.

Opioids may be an effective treatment for chronic and acute pain when properly used (1). However, receiving an opioid prescription in the emergency department (ED) has been identified as a potential risk factor for long-term use (2). Between 2010-2011 and 2016-2017, the percentage of opioids prescribed at ED discharge decreased from 21.5% to 14.6% (3,4). This report provides more recent changes in rates and percentages of opioids prescribed to adults (aged 18 and over) at discharge from the ED by patient and visit characteristics through 2020, using data from the National Hospital Ambulatory Medical Care Survey (NHAMCS).

Spinal cord injury (SCI) can lead to devastating autonomic dysfunction. One of the most challenging issues for functional repair in SCI is the secondary damage caused by the increased release of glutamate and free Ca from injured cells. Here, an in situ assembled trapping gel (PF-SA-GAD) is developed to sweep glutamate and Ca , promoting SCI repair. The hydrogel solution is a mixture of recombinant glutamate decarboxylase 67 (rGAD67) protein, sodium alginate (SA), and pluronic F-127 (PF-127). After intrathecal administration, temperature-sensitive PF-127 promoted in situ gelation. Glutamate (Glu) is captured and decarboxylated by rGAD67 into γ-aminobutyric acid (GABA). SA reacted with the free Ca to generate gellable calcium alginate. Thereby, this in situ trapping gel retarded secondary neuron injury caused by Glu and free Ca during SCI. In rat models of SCI, PF-SA-GAD reduces the lesion volume and inflammatory response after SCI, restores the motor function of rats with SCI. Together, the in situ assembled trapping gel is a long-term effective and minimally invasive sweeper for the direct elimination of glutamate and Ca from injury lesions and can be a novel strategy for SCI repair by preventing secondary injury.

Temporomandibular disorder (TMD) is a common condition that frequently transitions to chronic symptoms. Experimental pain models that mimic the symptoms of clinical TMD may be useful in understanding the mechanisms, and sex differences, present in this disorder. Here we aimed to comprehensively characterise the nature and time-course of pain, functional impairment and hyperalgesia induced by repeated intramuscular injection of nerve growth factor (NGF) into the masseter muscle, and to investigate sex differences in the NGF-induced pain experience.

Over the past three decades, there has been a significant growth in the use of natural products, with approximately 80% of individuals using them for some aspect of primary healthcare. Our laboratories have identified and studied natural compounds with analgesic effects from dry land plants or their associated fungus during the past ten years. Here, we isolated and characterized thirteen betulin analogs and fifteen betulinic acid analogs for their capacity to prevent calcium influx brought on by depolarization in sensory neurons. The in vitro inhibition of voltage-gated calcium channels by the top drugs was then assessed using whole cell patch clamp electrophysiology. In vivo experiments, conducted at two sites, evaluated the best compound in acute and tonic, neuropathic, inflammatory, post-operative and visceral models of pain. We found that the betulinic acid analog inhibited calcium influx in rat dorsal root ganglion neurons by inhibiting N- (CaV2.2) and T- (CaV3) type voltage-gated calcium channels. Moreover, intrathecal delivery of analog had analgesic activity in both spared nerve injury model of neuropathic pain and acute and tonic pain induced by formalin. The results presented herein highlight the potential antinociceptive properties of betulinic acid analog and set the stage for the development of novel non-opioid pain therapeutics based on the triterpenoid scaffold of betulinic acid.

Erythrodermic atopic dermatitis (AD) is a severe AD subtype defined by extensive skin involvement, leading to complications and sometimes hospitalization.

The underlying mechanisms of spinal cord injury (SCI)-induced chronic pain involve dysfunctional GABAergic signaling and enhanced NMDA signaling. Our previous studies showed that SCI hypersensitivity in rats can be attenuated by recombinant rat GABAergic cells releasing NMDA blocker serine-histogranin (SHG) and by intensive locomotor training (ILT). The current study combines these approaches and evaluates their analgesic effects on a model of SCI pain in rats. Cells were grafted into the spinal cord at 4 weeks post-SCI to target the chronic pain, and ILT was initiated 5 weeks post-SCI. The hypersensitivity was evaluated weekly, which was followed by histological and biochemical assays. Prolonged effects of the treatment were evaluated in subgroups of animals after we discontinued ILT. The results show attenuation of tactile, heat and cold hypersensitivity in all of the treated animals and reduced levels of proinflammatory cytokines IL1β and TNFα in the spinal tissue and CSF. Animals with recombinant grafts and ILT showed the preservation of analgesic effects even during sedentary periods when the ILT was discontinued. Retraining helped to re-establish the effect of long-term training in all of the groups, with the greatest impact being in animals with recombinant grafts. These findings suggest that intermittent training in combination with cell therapy might be an efficient approach to manage chronic pain in SCI patients.

Classically, to electrically excite C-nociceptors, rectangular pulses are used with a duration close to the estimated chronaxie of C-fibres (about 2 ms). Recent results using slow depolarizing stimuli suggest longer chronaxies. We therefore set out to optimize C-fiber stimulation based on recordings of single C-nociceptors in-vivo and C-fiber compound-action-potentials (C-CAP) ex-vivo using half-sine shaped stimuli of durations between 1 and 250ms. Single fiber (n=45) recording in pigs revealed high chronaxie values for C-touch fibers (15.8 ms), polymodal- (14.2 ms) and silent-nociceptors (16.8 ms). Activation thresholds decreased 2-3fold in all fiber classes when increasing the duration of half-sine pulses from 1 to 25 ms (p<0.05). C-CAPs strength-duration curves of the pig saphenous nerve (n=7) showed the highest sensitivity for half-sine durations between 10 and 25 ms. Half-maximum currents for C-CAPS were reduced 3fold compared to rectangular pulses (p<0.01) whereas the opposite was found for A-fiber compound action potentials. Psychophysics in humans (n=23) revealed that half-sine stimulus durations >10 ms reduced detection thresholds, pain thresholds and stimulus current amplitudes required to generate a pain rating of 3 on an 11-point Numeric Rating Scale (NRS) as compared to 1 ms rectangular pulses (p<0.05). Increasing the duration from 1 to 25 ms led to a 4fold amplitude reduction for pain-thresholds and stimuli caused an axon-reflex flare. Excitability of single polymodal nociceptors in animals paralleled human psychophysics and we conclude optimized half-sine pulses facilitate C-nociceptor activation. PERSPECTIVE: Electrical stimulation with longer lasting half-sine wave pulses preferentially activates C-nociceptors and changes in the strength duration curve may identify nociceptor hyperexcitability in patients with neuropathic pain.

HomeCageScan (HCS) is an automated behavioral scoring system that can be used to classify and quantify rodent behaviors in the home cage. Although HCS has been used for a number of inducible models of severe pain, little has been done to test this system in clinically relevant genetic disease models associated with chronic pain such as Fabry disease. Rats with Fabry disease exhibit mechanical hypersensitivity, however, it is unclear if these rodents also exhibit ongoing non-evoked pain. Therefore, we analyzed HCS data from male and female rats with Fabry disease. Using hierarchical clustering and principal component analysis, we found both sex and genotype differences in several home cage behaviors. Additionally, we used hierarchical clustering to derive behavioral clusters in an unbiased manner. Analysis of these behavioral clusters showed that primarily female Fabry animals moved less, spent less time caring for themselves (e.g., less time spent grooming and drinking), explored less, and slept more; changes that are similar to lifestyle changes observed in patients with long lasting chronic pain. We also show that sniffing, one of the exploratory behaviors that is depressed in Fabry animals, can be partly restored with the analgesic gabapentin, suggesting that depressed sniffing may reflect ongoing pain. Therefore, this approach to HCS data analysis can be used to assess drug efficacy in Fabry disease and potentially other genetic and inducible rodent models associated with persistent pain.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used analgesics to treat inflammatory pain. Despite their efficacy, recent studies show that NSAID use in early acute pain can prolong pain and inflammation and delay their resolution. We suggest using analgesics without inflammation-related properties in early acute pain instead of NSAIDs.

Despite the available knowledge on underlying mechanisms and the development of several therapeutic strategies, optimal management of postoperative pain remains challenging. This pre-clinical study hypothesizes that, by promoting an anti-inflammatory scenario, pre-emptive administration of IMT504, a non-coding, non-CpG oligodeoxynucleotide with immune modulating properties, will reduce postincisional pain, also facilitating therapeutic opioid-sparing. Male adult Sprague-Dawley rats with unilateral hindpaw skin-muscle incision received pre-emptive (48 h and 24 h prior to surgery) or postoperative (6h after surgery) subcutaneous vehicle (saline) or IMT504. Various groups of rats were prepared for pain-like behaviour analyses, including subgroups receiving morphine or naloxone, as well as for flow-cytometry or quantitative RT-PCR analyses of the spleen and hindpaws (for analysis of inflammatory phenotype). Compared to vehicle-treated rats, pre-emptive IMT504 significantly reduced mechanical allodynia by 6 h after surgery, and accelerated recovery of basal responses from 72 h after surgery and onwards. Cold allodynia was also reduced by IMT504. Postoperative administration of IMT504 resulted in similar positive effects on pain-like behaviour. In IMT504-treated rats, 3 mg/kg morphine resulted in comparable blockade of mechanical allodynia as observed in vehicle-treated rats receiving 10 mg/kg morphine. IMT504 significantly increased hindpaw infiltration of mesenchymal stem cells, CD4+T and B cells, and caused upregulated or downregulated transcript expressions of interleukin-10 and interleukin-1β, respectively. Also, IMT504 treatment targeted the spleen, with upregulated or downregulated transcript expressions, 6 h after incision, of interleukin-10 and interleukin-1β, respectively. Altogether, pre-emptive or postoperative IMT504 provides protection against postincisional pain, through participation of significant immunomodulatory actions, and exhibiting opioid-sparing effects.

It is currently unknown which pain-related factors contribute to long-term disability and poorer perceived health among older adults with chronic low back pain (LBP). This investigation sought to examine the unique influence of movement-evoked pain (MeP) and widespread pain (WP) on longitudinal health outcomes (i.e., gait speed, perceived disability, and self-efficacy) in 250 older adults with chronic LBP. MeP was elicited with three standardized functional tests, while presence of WP was derived from the McGill Pain Map. Robust regression with HC3 standard errors was used to examine associations between these baseline pain variables and health outcomes at 12-month follow-up. Covariates for these models included age, sex, body mass index, resting and recall LBP intensity, LBP duration, depression, pain catastrophizing, and baseline outcome (e.g., baseline gait speed). Greater MeP was independently associated with worse 12-month LBP-related disability (b=0.384, t=2.013, p=0.046) and poorer self-efficacy (b=-0.562, t=-2.074, p=0.039); but not gait speed (p>0.05). In contrast, WP and resting and recall LBP intensity were not associated with any prospective health outcome after adjustment (all p>0.05). Compared to WP and resting and recall LBP intensity, MeP is most strongly related to longitudinal health outcomes in older adults with chronic LBP. Perspective: This article establishes novel independent associations between MeP and worse perceived disability and self-efficacy at 12-months in older adults with chronic LBP. MeP likely has biopsychosocial underpinnings and consequences and may therefore be an important determinant of health outcomes in LBP and other geriatric chronic pain populations.

The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based -Cre knock-in transgenic rat that provides cell-type specific genetic access to MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the -Cre knock-in rats to study the involvement of nucleus accumbens (NAc) MOR-expressing cells in heroin self-administration in male and female rats.Using RNAscope, autoradiography, and fluorescence hybridization chain reaction (HCR-FISH), we found no differences in expression in NAc, dorsal striatum (DS), and dorsal hippocampus, or MOR receptor density (except DS) or function between -Cre knock-in rats and wildtype littermates. HCR-FISH assay showed that is highly co-expressed with (95-98%). There were no genotype differences in pain responses, morphine analgesia and tolerance, heroin self-administration, and relapse-related behaviors. We used the Cre-dependent vector AAV1-EF1a-Flex-taCasp3-TEVP to lesion NAc MOR-expressing cells. We found that lesions decreased acquisition of heroin self-administration in male -Cre rats and had a stronger inhibitory effect on the effort to self-administer heroin in female -Cre rats.The validation of an -Cre knock-in rat enables new strategies for understanding the role of MOR-expressing cells in rat models of opioid addiction, pain-related behaviors, and other opioid-mediated functions. Our initial mechanistic study indicates that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in male and female rats.The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based -Cre knock-in transgenic rat that provides cell-type specific genetic access to brain MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the -Cre knock-in rats to show that lesioning nucleus accumbens MOR-expressing cells had different effects on heroin self-administration in males and females. The new -Cre rats can be used to study the role of brain MOR-expressing cells in animal models of opioid addiction, pain-related behaviors, and other opioid-mediated functions.

Repetitive movements (RM) are a main risk factor for musculoskeletal pain, which is partly explained by the overloading of musculoskeletal structures. However, RM may also drive brain plasticity, leading to maladaptive changes in sensorimotor areas and altered pain processing. This study aimed to understand whether individuals performing extensive RM (musicians) exhibit altered brain processing to prolonged experimental muscle pain. Nineteen healthy musicians and 20 healthy non-trained controls attended three sessions (Day1-Day3-Day8). In each session, event-related potentials (ERPs) to non-nociceptive superficial and nociceptive intra-epidermal electrical stimulation, reaction times (RTs), electrical detection thresholds (EDTs), and pressure pain thresholds (PPTs) were recorded. In all participants, prolonged muscle pain was induced by intramuscular injection of nerve growth factor (NGF) into the right first dorsal interosseous muscle at the end of Day1. Pain intensity was assessed on a numerical rating scale (NRS) and was lower in musicians compared to non-musicians (p<0.007). Compared with Day1, NGF reduced PPTs on Day3-Day8 (p<0.001) and non-nociceptive P200 and P300 ERP amplitudes on Day8 (p<0.044) in both groups. Musicians compared to controls showed secondary hyperalgesia to electrical stimulation on Day3-Day8 (p<0.004) and reduced nociceptive P200 ERP amplitudes on Day8 (p<0.005). Across participants, ERP components correlated with pain detection (RTs), sensitivity (PPTs and EDTs), and severity (NRS), (all p<0.043). In musicians, the amount of weekly training was associated with higher NGF-induced NRS pain scores on Day3-Day8 (p<0.037). These results show that repetitive sensorimotor training leads to brain changes in the processing of prolonged pain, biasing the cortical response to nociceptive inputs.

Transient receptor potential vanilloid 1 (TRPV1), a receptor for capsaicin and noxious heat, has been one of the most compelling targets for analgesics. However, systemic inhibition of TRPV1 is an impractical approach as a pain killer, since systemic antagonism induces hyperthermia. Two articles in this issue of the JCI report phenotypes from separate, rare missense mutations of human TRPV1. He, Zambelli, and colleagues investigated TRPV1K710N, which showed reduced functionality, while Katz, Zaguri, and co-authors reported on TRPV1N331K, which led to a complete functional knockout. The findings provide insights that will improve our understanding of the endogenous functions of TRPV1 in humans and may facilitate a rational TRPV1-targeting approach to achieve hyperthermia-free analgesia.

Patients with chronic pain often receive long-term opioid therapy (LOT), which places them at risk of opioid use disorder and overdose. This presents the need for alternative or companion treatments; however, few studies on the association of medical cannabis (MC) with reducing opioid dosages exist.

Gastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including those of the breast, prostate, pancreas, lung, and central nervous system. Additionally, it also mediates non-histaminergic itch and pathological itch conditions in mice. Thus, GRPR could be an attractive target for cancer and itch therapy. Here, we report the inactive state crystal structure of human GRPR in complex with the non-peptide antagonist PD176252, as well as two active state cryo-electron microscopy (cryo-EM) structures of GRPR bound to the endogenous peptide agonist gastrin-releasing peptide and the synthetic BBN analog [D-Phe, β-Ala, Phe, Nle] Bn (6-14), in complex with G heterotrimers. These structures revealed the molecular mechanisms for the ligand binding, receptor activation, and G proteins signaling of GRPR, which are expected to accelerate the structure-based design of GRPR antagonists and agonists for the treatments of cancer and pruritus.

The search towards more objective outcome measurements and consequently surrogate markers for pain started decades ago; however, no generally accepted biomarker for pain has qualified yet. The goal is to explore the value of heart rate variability (HRV) as surrogate marker for pain intensity chronic pain setting. Pain intensity scores and HRV were collected in 366 patients with chronic pain, through a cross-sectional multicenter study. Pain intensity was measured with both the visual analogue scale and numeric rating scale, whereas 16 statistical HRV parameters were derived. Canonical correlation analysis was performed to evaluate the correlation between the dependent pain variables and the HRV parameters. Surrogacy was determined for each HRV parameter with point estimates between 0 and 1 whereby values close to 1 indicate a strong association between the surrogate and the true endpoint at the patient level. Weak correlations were revealed between HRV parameters and pain intensity scores. The highest surrogacy point estimate was found for mean heart rate as marker for average pain intensity on the numeric rating scale with point estimates of 0.0961 (95% confidence interval [CI] 0.0384-0.1537) and 0.0209 (95% CI 0-0.05) for patients without medication use and with medication, respectively. This study indicated that HRV parameters as separate entities are no suitable surrogacy candidates for pain intensity, in a population of chronic pain patients. Further potential surrogate candidates and clinical robust true endpoints should be explored, to find a surrogate measure for the highly individual pain experience.

Irritable bowel syndrome (IBS) is the most prevalent disorder of brain-gut interactions that affects between 5 and 10% of the general population worldwide. The current symptom criteria restrict the diagnosis to recurrent abdominal pain associated with altered bowel habits, but the majority of patients also report non-painful abdominal discomfort, associated psychiatric conditions (anxiety and depression), as well as other visceral and somatic pain-related symptoms. For decades, IBS was considered an intestinal motility disorder, and more recently a gut disorder. However, based on an extensive body of reported information about central, peripheral mechanisms and genetic factors involved in the pathophysiology of IBS symptoms, a comprehensive disease model of brain-gut-microbiome interactions has emerged, which can explain altered bowel habits, chronic abdominal pain, and psychiatric comorbidities. In this review, we will first describe novel insights into several key components of brain-gut microbiome interactions, starting with reported alterations in the gut connectome and enteric nervous system, and a list of distinct functional and structural brain signatures, and comparing them to the proposed brain alterations in anxiety disorders. We will then point out the emerging correlations between the brain networks with the genomic, gastrointestinal, immune, and gut microbiome-related parameters. We will incorporate this new information into a systems-based disease model of IBS. Finally, we will discuss the implications of such a model for the improved understanding of the disorder and the development of more effective treatment approaches in the future.

The interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions.

Alcohol use, tobacco use, and other substance use often co-occur with depression, anxiety, and chronic pain, forming a constellation of alcohol, substance, and mood-related (CASM) conditions that disproportionately affects people with HIV in the USA. We used a microsimulation model to evaluate how alternative screening strategies accounting for CASM interdependence could affect life expectancy in people with HIV in the USA.

Vascular endothelial growth factor A (VEGF-A) is a pro-nociceptive factor that causes neuronal sensitization and pain. We reported that blocking the interaction between the membrane receptor Neuropilin 1 (NRP1) and VEGF-A blocked VEGF-A mediated sensory neuron hyperexcitability and reduced mechanical hypersensitivity in a rodent chronic neuropathic pain model. These findings identified the NRP1-VEGF-A signaling axis for therapeutic targeting of chronic pain. In an in-silico screening of ∼480K small molecules binding to the extracellular b1b2 pocket of NRP1, we identified nine chemical series, with six compounds disrupting VEGF-A binding to NRP1. The small molecule with greatest efficacy, 4'-methyl-2'-morpholino-2-(phenylamino)-[4,5'-bipyrimidin]-6(1H)-one, designated NRP1-4, was selected for further evaluation. In cultured primary sensory neurons, VEGF-A enhanced excitability and decreased firing threshold, which was blocked by NRP1-4. Additionally, NaV1.7 and CaV2.2 currents, and membrane expression, were potentiated by treatment with VEGF-A and this potentiation was blocked by NRP1-4 co-treatment. NRP1-4 reduced VEGF-A-mediated increases in the frequency and amplitude of spontaneous excitatory postsynaptic currents in dorsal horn of the spinal cord. NRP1-4 did not bind to over 300 GPCRs and receptors including human opioids receptors, indicating a favorable safety profile. In rats with spared nerve injury (SNI)-induced neuropathic pain, intrathecal administration of NRP1-4 significantly attenuated mechanical allodynia. Intravenous treatment with NRP1-4 reversed both mechanical allodynia and thermal hyperalgesia in rats with L5/L6 spinal nerve ligation (SNL)-induced neuropathic pain. Collectively, our findings show that NRP1-4 is a first-in-class compound targeting the NRP1-VEGF-A signaling axis to control voltage-gated ion channel function, synaptic activity, and curb chronic pain.

Reduced conditioned pain modulation (CPM) and psychological distress co-occur frequently in many pain conditions. This study explored whether common negative pain cognitions and emotional factors were related to lower CPM in individuals across the spectrum from acute to chronic pain. Previously collected data on the CPM effect, pain-related cognitions (fear of movement, pain catastrophizing), and emotional distress (depression, anxiety) from questionnaires in 1142 individuals with acute, subacute, or chronic pain were used. The presence of negative psychological factors was dichotomized according to cut-off values for questionnaires. Associations between the presence of each negative psychological factor and the amplitude of pain reduction in the CPM paradigm was explored with Generalized Linear Models adjusted for sex, age, body mass index, and pain duration. A secondary analysis explored the cumulative effect of psychological factors on CPM. When dichotomized according to cut-off scores, 20% of participants were classified with anxiety, 19% with depression, 36% with pain catastrophizing, and 48% with fear of movement. The presence of any negative psychological factor nor the cumulative sum of negative psychological factors were associated with lower CPM (individual factor: β between -0.15 and 0.11, P≥0.08; Total: β between –0.27 and -0.12, P≥0.06). Despite the common observation of psychological factors and reduced CPM in musculoskeletal pain, these data challenge the assumption of a linear relationship between these variables across individuals with acute, subacute, and chronic pain. Arguably, there was a non-significant tendency for associations in non-expected directions, which should be studied in a more homogenous population.

Surgery is often advised when conservative treatment fails in musculoskeletal pain conditions, but a substantial proportion still suffers chronic pain after surgery. Somatosensory processing system (SPS) signs were previously studied as potential predictors for chronic postsurgical pain, but results are inconsistent. Therefore, studying the evolution of SPS signs could be of added value. The aim was to summarize all studies that measured how SPS signs evolved after nociceptive targeted surgery in musculoskeletal disorders, and to find pre-, peri- and postoperative predictors for the evolution of these SPS signs. Data was summarized, and risk of bias and level of evidence and recommendation were determined. Twenty-one studies were included. Five scored a low, three a moderate, and 13 a high risk of bias. In general, no consistent evolution of SPS signs comparing pre- and postoperative values and predictors for this evolution in musculoskeletal disorders could be found. In most cases, static quantitative sensory testing (QST) did not change or conflicting results were found. On the other hand, dynamic QST mostly improved after surgery. Worthfully mentioning is that worsening of SPS signs was only seen at a follow-up of < 3 months after surgery, that conclusions are stronger when evaluating dynamic QST with a follow up of ≥ 3 months after surgery, and that pain improvement postsurgery was an important predictor. Future high quality research should focus on the evolution of SPS signs after nociceptive targeted surgery, accounting for pain improvement groups and focusing on pre, peri- and postoperative predictors of this evolution.

Quantitative sensory testing (QST) is increasingly used in pediatric chronic pain; however, assessment in youth with acute musculoskeletal (MSK) pain is limited. This study evaluated the feasibility, reliability, and sources of variability of a brief QST protocol in two clinical samples of youth with acute MSK pain. Participants were 277 youth (Mage=14.5 years, SD=2.0, range=11-18 years, 59% female, 83% non-Hispanic) across 3 geographic study sites who completed a QST protocol assessing pressure and thermal pain sensitivity, temporal summation of pain (TSP), and conditioned pain modulation (CPM) 8-weeks post MSK surgery (n=100) or within 4-weeks following an acute MSK injury (n=177). High feasibility was demonstrated by protocol completion rates ranging from 97.5%-100% for each task, with 95.3% of youth completing all tasks. Reliability was high, with reliability coefficients > 0.97 for 7 out of 8 QST parameters and minimal influence of examiner or participating site effects. Younger youth had lower pressure and heat pain thresholds (11-12 vs. 13-18 years, d=-0.80 to -0.56) and cold pain tolerance (d=-0.33). Hispanic youth had higher pressure and heat pain thresholds (d=0.37-0.45) and pain ratings for cold pain tolerance (d=0.54) compared to non-Hispanic youth. No significant differences were observed in QST values by sex or personal contextual factors at time of assessment (momentary pain, menstrual period, use of pain medications). Overall findings demonstrate feasibility of a brief QST protocol with youth with diverse acute MSK pain and data provide initial support for the reliability of this QST protocol for multisite research studies.

The synthetic peptide ERα17p (sequence: PLMIKRSKKNSLALSLT), which corresponds to the 295-311 region of the human estrogen receptor α (ERα), induces apoptosis in breast cancer cells. In mice and at low doses, it promotes not only the decrease of the size of xenografted triple-negative human breast tumors, but also anti-inflammatory and anti-nociceptive effects. Recently, we have shown that these effects were due to its interaction with the seven-transmembrane G protein-coupled estrogen receptor GPER. Following modeling studies, the C-terminus of this peptide (sequence: NSLALSLT) remains compacted at the entrance of the GPER ligand-binding pocket, whereas its N-terminus (sequence: PLMI) engulfs in the depth of the same pocket. Thus, we have hypothesized that the PLMI motif could support the pharmacological actions of ERα17p. Here, we show that the PLMI peptide is, indeed, responsible for the GPER-dependent antiproliferative and anti-nociceptive effects of ERα17p. By using different biophysical approaches, we demonstrate that the NSLALSLT part of ERα17p is responsible for aggregation. Overall, the tetrapeptide PLMI, which supports the action of the parent peptide ERα17p, should be considered as a hit for the synthesis of new GPER modulators with dual antiproliferative and anti-nociceptive actions. This study highlights also the interest to modulate GPER for the control of pain.

A major concern with cannabis-based medicines and medical cannabis (CbM) is the risk of abuse and dependence. The face validity of the International Classification of Diseases (ICD-10) criteria for cannabis dependence in patients prescribed CbM for chronic pain has not been assessed.

The availability of long-term (>2 years) safety outcomes of spinal cord stimulation (SCS) remains limited. We evaluated safety in a global SCS registry for chronic pain. Participants were prospectively enrolled globally at 79 implanting centers and followed out to 3 years after device implantation. Of 1881 participants enrolled, 1289 received a permanent SCS implant (1776 completed trial). The annualized rate of device explant was 3.5% (all causes), and 1.1% due to inadequate pain relief. Total incidence of device explantation >3 years was 7.6% (n = 98). Of these, 32 subjects (2.5%) indicated inadequate pain relief as cause for removal. Implant site infection (11 events) was the most common device-related serious adverse event (<1%). This prospective, global, real-world study demonstrates a high-level of safety for SCS with low rate of explant/serious adverse events. : NCT01719055 (ClinicalTrials.gov).

The primary aim of this observational study was to determine the incidence of trigeminal neuralgia in a county in central Sweden. The secondary aim was to investigate TN characteristic including the affected side and nerve branches.

Urological chronic pelvic pain syndrome (UCPPS) manifests as pelvic pain with frequent urination and has a 10% prevalence rate without effective therapy. Nanoceria (cerium oxide nanoparticles [CNPs]) were synthesized in this study to achieve potential long-term pain relief, using a commonly used UCPPS mouse model with cyclophosphamide-induced cystitis. Transcriptome sequencing analysis revealed that serpin family B member 2 (SerpinB2) was the most upregulated marker in mouse bladder, and SerpinB2 was downregulated with CNP pretreatment. The transcriptome sequencing analysis results agreed with quantitative polymerase chain reaction and western blot analysis results for the expression of related mRNAs and proteins. Analysis of Gene Expression Omnibus (GEO) datasets revealed that SerpinB2 was a differentially upregulated gene in human UCPPS. In vitro SerpinB2 knockdown downregulated proinflammatory chemokine expression (chemokine receptor CXCR3 and C-X-C motif chemokine ligand 10) upon treatment with 4-hydroperoxycyclophosphamide. In conclusion, CNP pretreatment may prevent the development of UCPPS, and reactive oxygen species (ROS) scavenging and SerpinB2 downregulation may modulate the immune response in UCPPS.

Since the discovery of STING in 2008, numerous studies have investigated its functions in immunity, inflammation, and cancer. STING activates downstream molecules including IFN-I, NLRP3, and NF-κB. The STING-IFN-I pathway plays a vital role in nociception. After receiving the upstream signal, STING is activated and induces the expression of IFN-I, and after paracrine and autocrine signaling, IFN-I binds to IFN receptors. Subsequently, the activity of ion channels is inhibited by TYK2, which induces an acute antinociceptive effect. JAK activates PIK3 and MAPK-MNK-eIF4E pathways, which sensitize nociceptors in the peripheral nervous system. In the mid-late stage, the STING-IFN-I pathway activates STAT, increases pro-inflammatory and anti-inflammatory cytokines, inhibits ER-phagy, and promotes microglial M1-polarization in the central nervous system, leading to central sensitization. Thus, the STING-IFN-I pathway may exert complex effects on nociception at various stages, and these effects require further comprehensive elucidation. Therefore, in this review, we systematically summarized the mechanisms of the STING-IFN-I pathway and discussed its function in nociception.

Visceral pain is a complex and heterogeneous disorder that is considered more prominent compared to somatic pain, due to its multiple and complex causes and accompanying emotional and mood disorders. Research has become increasingly extensive over the years, but a bibliometric analysis of this field is lacking. The aim of this study was to analyze global research trends in visceral pain over the past 40 years through visual analysis.

Histamine has been postulated to play a role in atopic dermatitis via histamine receptor 4, mediating pruritic and inflammatory effects. The H4R antagonist adriforant (PF-3893787 or ZPL389) indicated clinical efficacy in a Ph2a study in atopic dermatitis. Preclinical investigations of adriforant had been scarce as experiments in transfectants with H4R from several species suggested partial agonism, not seen in human cells.

This preclinical systematic review aimed to determine the effectiveness of different types and doses of exercise on pain behaviour and biomarkers in preclinical models of focal neuropathic pain. We searched MEDLINE, EMBASE, Web of Science, PubMed, SCOPUS, CINAHL and Cochrane library from inception to November 2022 for preclinical studies evaluating the effect of exercise compared to control interventions on neuropathic pain behaviour after experimental sciatic nerve injury. If possible, data were meta-analysed using random effect models with inverse-variance weighting. Thirty-seven studies were included and 26 meta-analysed. Risk of bias (SYRCLE tool) remained unclear in most studies and reporting quality (CAMARADES) was variable. Exercise reduced mechanical (SMD 0.53 (95% CI 0.31, 0.74), p= 0.0001, I=0%, n=364), heat (0.32 (0.07,0.57), p=0.01, I=0%, n=266) and cold hypersensitivity (0.51 (0.03, 1.0), p=0.04, I=0%, n=90) compared to control interventions. No relationship was apparent between exercise duration or intensity and antinociception. Exercise modulated biomarkers related to different systems (e.g., immune system, neurotrophins). Whereas firm conclusions are prevented by the use of male animals only, variable reporting quality and unclear risk of bias in many studies, our results suggest that aerobic exercise is a promising tool in the management of focal neuropathic pain. Registration PROSPERO CRD42021231286. Perspective: This systematic review and meta-analysis demonstrates that aerobic exercise reduces neuropathic pain-related behavior in preclinical models of sciatic nerve injury. This effect is accompanied by changes in biomarkers associated with inflammation and neurotrophins among others. These results could help to develop exercise interventions for patients with neuropathic pain.

Dysfunctional sensory processing is described in migraine. This study aimed to evaluate visual perception in patients with migraine without aura using the visual temporal discrimination (VTD) test.

Opioids are often first-line analgesics in pain therapy. However, prolonged use of opioids causes paradoxical pain, termed "opioid-induced hyperalgesia (OIH)." The infralimbic medial prefrontal cortex (IL-mPFC) has been suggested to be critical in inflammatory and neuropathic pain processing through its dynamic output from layer V pyramidal neurons. Whether OIH condition induces excitability changes of these output neurons and what mechanisms underlie these changes remains elusive. Here, with combination of patch-clamp recording, immunohistochemistry, as well as optogenetics, we revealed that IL-mPFC layer V pyramidal neurons exhibited hyperexcitability together with higher input resistance. In line with this, optogenetic and chemogenetic activation of these neurons aggravates behavioral hyperalgesia in male OIH rats. Inhibition of these neurons alleviates hyperalgesia in male OIH rats but exerts an opposite effect in male control rats. Electrophysiological analysis of hyperpolarization-activated cation current (Ih) demonstrated that decreased Ih is a prerequisite for the hyperexcitability of IL-mPFC output neurons. This decreased Ih was accompanied by a decrease in HCN1, but not HCN2, immunolabeling, in these neurons. In contrast, the application of HCN channel blocker increased the hyperalgesia threshold of male OIH rats. Consequently, we identified an HCN-channel-dependent hyperexcitability of IL-mPFC output neurons, which governs the development and maintenance of OIH in male rats.

Individual sensory neurons can be tuned to many stimuli, each driving unique, stimulus-relevant behaviors, and the ability of multimodal nociceptor neurons to discriminate between potentially harmful and innocuous stimuli is broadly important for organismal survival. Moreover, disruptions in the capacity to differentiate between noxious and innocuous stimuli can result in neuropathic pain. larval Class III (CIII) neurons are peripheral noxious cold nociceptors and innocuous touch mechanosensors; high levels of activation drive cold-evoked contraction (CT) behavior, while low levels of activation result in a suite of touch-associated behaviors. However, it is unknown what molecular factors underlie CIII multimodality. Here, we show that the TMEM16/anoctamins and (; ) are required for cold-evoked CT, but not for touch-associated behavior, indicating a conserved role for anoctamins in nociception. We also evidence that CIII neurons make use of atypical depolarizing chloride currents to encode cold, and that overexpression of -a fly homologue of -results in phenotypes consistent with neuropathic sensitization, including behavioral sensitization and neuronal hyperexcitability, making CIII neurons a candidate system for future studies of the basic mechanisms underlying neuropathic pain.

Osteoarthritis (OA) is a leading cause of chronic pain and disability, not only in the United States but also worldwide. The burden of OA is higher in women than in men. Estrogen as a possible explanation for observed sex differences in OA has not been definitively established. The purpose of this review was to summarize the results from studies of estrogen, estrogen depletion and treatment, and their impact on knee, hip, hand, and spine OA. We conducted a targeted review of the literature using PubMed. Although several studies show that hormone replacement therapy has the potential to be protective of OA for some joints, there are studies that showed no protective effect or even adverse effect. Taken together, the evidence for the protective effect of estrogen therapy depends on OA joint, OA outcome, and study design. Although this area has been studied for decades, more exclusively since the 1990s, there is a lack of high-quality experimental research in this topic. The lack of definitive conclusion on whether estrogen can play a role in the development in OA of either the knee, hip, spine, or hand is often in part due to the noncomparability of studies existing within the literature. Differences in diagnostic criteria, imaging modalities, populations studied, study designs, and outcome measures, as well as random error, have all contributed to inconclusive evidence. Future research on the role of estrogen in OA is needed, particularly as global demographic shifts in increasing overweight/obesity prevalence and ageing populations may contribute to widening OA-related health inequalities.

To assess the clinical efficacy of remote electrical neuromodulation (REN), used every other day, for the prevention of migraine.

To systemically review clinical studies investigating the role of prolactin and its receptors in headache and migraine.

In patients with sickle cell disease (SCD), negative physical and emotional experiences result from intense chronic and acute pain episodes, but factors underlying these, and their interactions, are not well understood. The arginine vasopressin receptor 1a gene () single nucleotide polymorphism rs10877969 has been previously associated with aspects of acute pain and stress related pain. In this study, we tested for associations between this SNP, thermal and pressure pain thresholds, clinical pain, and stress in people with SCD.

Antiretroviral therapy has significantly reduced morbidity and mortality in people with HIV. Despite being virally suppressed, sleep disturbances, chronic pain, and neurocognitive impairments persist which can negatively impact quality of life for people with HIV. This article presents relevant literature related to sleep disturbances and chronic pain in people with HIV. The potential impact of these comorbidities on cognition is discussed with implications for managing HIV-associated neurocognitive disorder (HAND).

Rheumatoid arthritis (RA) is a common systematic, chronic inflammatory, autoimmune, and polyarticular disease, causing a range of clinical manifestations, including joint swelling, redness, pain, stiffness, fatigue, decreased quality of life, progressive disability, cardiovascular problems, and other comorbidities. Strong evidence has shown that exercise is effective for RA treatment in various clinical domains. Exercise training for relatively longer periods (e.g., ≥ 12 weeks) can decrease disease activity of RA. However, the mechanism underlying the effectiveness of exercise in reducing RA disease activity remains unclear. This review first summarizes and highlights the effectiveness of exercise in RA treatment. Then, we integrate current evidence and propose biological mechanisms responsible for the potential effects of exercise on immune cells and immunity, inflammatory response, matrix metalloproteinases, oxidative stress, and epigenetic regulation. However, a large body of evidence was obtained from the non-RA populations. Future studies are needed to further examine the proposed biological mechanisms responsible for the effectiveness of exercise in decreasing disease activity in RA populations. Such knowledge will contribute to the basic science and strengthen the scientific basis of the prescription of exercise therapy for RA in the clinical routine.

To develop and validate a Chronic Pelvic Pain Map in order to fill a gap in the need for a localized body map of the pelvic region.

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Fatigue, pain, headache, brain fog, anosmia, ageusia, mood symptoms, and sleep disorders are symptoms commonly experienced by people with post-COVID-19 condition. These symptoms could be considered as manifestations of central sensitization. The aim of this study is to evaluate whether there are indicators of central sensitization by using experimental pain measurements and to determine their association with patient-reported outcome measures (PROMs). A cross-sectional study including 42 patients after COVID-19 infection was conducted. The central sensitization inventory (CSI) was administered as a PROM to evaluate central-sensitization-associated symptoms. Pressure pain thresholds (PPT), temporal summation, and descending nociceptive pain inhibition (CPM) were assessed as experimental pain measurements. The median score on the CSI was 46.5 (Q1-Q3: 33-54). The presence of central-sensitization-associated symptoms was seen in 64.3% of patients based on the CSI (≥40/100 points). A deficient CPM was seen in 12% and 14% of patients when measured at the trapezius and rectus femoris, respectively. A negative correlation between pressure sensitivity on the rectus femoris and the CSI score (r = -0.36, 95%CI -0.13 to -0.65, = 0.007) was observed. Central-sensitization-associated symptoms were present in up to 64.3% of patients post-COVID-19 infection, based on a PROM, i.e., the CSI. A more objective evaluation of nociceptive processing through experimental pain measurements was less suggestive of indicators of central sensitization. Only a small negative correlation between pressure sensitivity and the CSI was observed, thereby pointing towards the discrepancy between the CSI and experimental pain measurements and presumably the complementary need for both to evaluate potential indicators of central sensitization in this population.

The use of the biopsychosocial model in primary care physiotherapy for chronic pain is far from the recommendations given in research and current guidelines. To understand why physiotherapists have difficulty implementing a biopsychosocial approach, more insight is needed on the barriers and facilitators. This scoping review aimed to investigate and map these barriers and facilitators that physiotherapists working in primary care reportedly face when treating patients with chronic musculoskeletal pain from a biopsychosocial perspective. Four electronic databases (PubMed, Embase, CINAHL and ERIC) and the grey literature were searched. Studies were included if they investigated the experiences of physiotherapists in the treatment of chronic pain from a biopsychosocial perspective in primary care. Extracted data were discussed and sub grouped in themes following a qualitative content analysis approach. To align with current use of theories on behavior change, the resulting themes were compared to the Theoretical Domains Framework. After screening, twenty-four studies were included. Eight groups of barriers and facilitators were identified, thematically clustered in six themes: knowledge, skills, and attitudes; environmental context and resources; role clarity; confidence; therapeutic alliance; and patient expectations. The results of this review can be used to inform the development of implementation programs.

Drugs enhancing the availability of noradrenaline are gaining prominence in the therapy of chronic neuropathic pain. However, underlying mechanisms are not well understood, and research has thus far focused on α2-adrenergic receptors and neuronal excitability. Adrenergic receptors are also expressed on glial cells, but their roles toward antinociception are not well deciphered. This study addresses the contribution of β2-adrenergic receptors (β2-ARs) to the therapeutic modulation of neuropathic pain in mice. We report that selective activation of β2-ARs with Formoterol inhibits pro-inflammatory signaling in microglia ex vivo and nerve injury-induced structural remodeling and functional activation of microglia in vivo. Systemic delivery of Formoterol inhibits behaviors related to neuropathic pain, such as mechanical hypersensitivity, cold allodynia as well as the aversive component of pain, and reverses chronically established neuropathic pain. Using conditional gene targeting for microglia-specific deletion of β2-ARs, we demonstrate that the anti-allodynic effects of Formoterol are primarily mediated by microglia. Although Formoterol also reduces astrogliosis at late stages of neuropathic pain, these functions are unrelated to β2-AR signaling in microglia. Our results underline the value of developing microglial β2-AR agonists for relief from neuropathic pain and clarify mechanistic underpinnings.

Chronic pain burdens patients and healthcare systems worldwide. Pain control remains urgently required. IL-17 (interleukin-17)-mediated neuroinflammation is of unique importance in spinal nociceptive transduction in pathological pain development. Recently, resolvin D2 (RvD2), as a bioactive, specialized pro-resolving mediator derived from docosahexaenoic acid, exhibits potent resolution of inflammation in several neurological disorders. This preclinical study evaluates the therapeutic potential and underlying targets of RvD2 in two mouse models of chronic pain, including sciatic nerve ligation-caused neuropathic pain and sarcoma-caused bone cancer pain. Herein, we report that repetitive injections of RvD2 (intrathecal, 500 ng) reduce the initiation of mechanical allodynia and heat hyperalgesia following sciatic nerve damage and bone cancer. Single exposure to RvD2 (intrathecal, 500 ng) attenuates the established neuropathic pain and bone cancer pain. Furthermore, systemic RvD2 (intravenous, 5 μg) therapy is effective in attenuating chronic pain behaviors. Strikingly, RvD2 treatment suppresses spinal IL-17 overexpression, chemokine CXCL1 release and astrocyte activation in mice undergoing sciatic nerve trauma and bone cancer. Pharmacological neutralization of IL-17 ameliorates chronic neuropathic pain and persistent bone cancer pain, as well as reducing spinal CXCL1 release. Recombinant IL-17-evoked acute pain behaviors and spinal CXCL1 release are mitigated after RvD2 administration. In addition, RvD2 treatment dampens exogenous CXCL1-caused transient pain phenotypes. Overall, these current findings identify that RvD2 therapy is effective against the initiation and persistence of long-lasting neuropathic pain and bone cancer pain, which may be through spinal down-modulation of IL-17 secretion, CXCL1 release and astrocyte activation.

Many human cardiovascular and neurological disorders (such as ischemia, epileptic seizures, traumatic brain injury, neuropathic pain, etc.) are associated with the abnormal functional activity of voltage-gated sodium channels (VGSCs/Nas). Many natural toxins, including the sea anemone toxins (called neurotoxins), are an indispensable and promising tool in pharmacological researches. They have widely been carried out over the past three decades, in particular, in establishing different Na subtypes functional properties and a specific role in various pathologies. Therefore, a large number of publications are currently dedicated to the search and study of the structure-functional relationships of new sea anemone natural neurotoxins-potential pharmacologically active compounds that specifically interact with various subtypes of voltage gated sodium channels as drug discovery targets. This review presents and summarizes some updated data on the structure-functional relationships of known sea anemone neurotoxins belonging to four structural types. The review also emphasizes the study of type 2 neurotoxins, produced by the tropical sea anemone , five structurally homologous and one unique double-stranded peptide that, due to the absence of a functionally significant Arg14 residue, loses toxicity but retains the ability to modulate several VGSCs subtypes.

Ketamine, a commonly used general anesthetic, can produce rapid and sustained antidepressant effect. However, the efficacy and safety of the perioperative application of ketamine on postoperative depression remains uncertain. We performed a meta-analysis to determine the effect of perioperative intravenous administration of ketamine on postoperative depression. Randomized controlled trials comparing ketamine with placebo in patients were included. Primary outcome was postoperative depression scores. Secondary outcomes included postoperative visual analog scale (VAS) scores for pain and adverse effects associated with ketamine. Fifteen studies with 1697 patients receiving ketamine and 1462 controls were enrolled. Compared with the controls, the ketamine group showed a reduction in postoperative depression scores, by a standardized mean difference (SMD) of -0.97, 95% confidence interval [CI, -1.27, -0.66], P < 0.001, I = 72% on postoperative day (POD) 1; SMD-0.65, 95% CI [-1.12, -0.17], P < 0.001, I = 94% on POD 3; SMD-0.30, 95% CI [-0.45, -0.14], P < 0.001, I = 0% on POD 7; and SMD-0.25, 95% CI [-0.38, -0.11], P < 0.001, I = 59% over the long term. Ketamine reduced VAS pain scores on POD 1 (SMD-0.93, 95% CI [-1.58, -0.29], P = 0.005, I = 97%), but no significant difference was found between the two groups on PODs 3 and 7 or over the long term. However, ketamine administration distinctly increased the risk of adverse effects, including nausea and vomiting (risk ratio [RR] 1.40, 95% CI [1.12, 1.75], P = 0.003, I = 30%), headache (RR 2.47, 95% CI [1.41, 4.32], P = 0.002, I = 19%), hallucination (RR 15.35, 95% CI [6.4, 37.34], P < 0.001, I = 89%), and dizziness (RR 3.48, 95% CI [2.68, 4.50], P < 0.001, I = 89%) compared with the controls. In conclusion, perioperative application of ketamine reduces postoperative depression and pain scores with increased risk of adverse effects.

Chronic low back pain (CLBP) is a disabling condition worldwide. In CLBP, neuroimaging studies demonstrate abnormal activities in cortical areas responsible for pain modulation, emotional, and sensory components of pain experience [i.e., pregenual and dorsal anterior cingulate cortex (pgACC, dACC), and somatosensory cortex (SSC), respectively]. This pilot study, conducted in a university setting, evaluated the feasibility, safety, and acceptability of a novel electroencephalography-based infraslow-neurofeedback (EEG ISF-NF) technique for retraining activities in pgACC, dACC and SSC and explored its effects on pain and disability. Participants with CLBP (n = 60), recruited between July'20 to March'21, received 12 sessions of either: ISF-NF targeting pgACC, dACC + SSC, a ratio of pgACC*2/dACC + SSC, or Placebo-NF. Descriptive statistics demonstrated that ISF-NF training is feasible [recruitment rate (7 participants/month), dropouts (25%; 20-27%), and adherence (80%; 73-88%)], safe (no adverse events reported), and was moderate to highly acceptable [Mean ± SD: 7.8 ± 2.0 (pgACC), 7.5 ± 2.7 (dACC + SCC), 8.2 ± 1.9 (Ratio), and 7.7 ± 1.5 (Placebo)]. ISF-NF targeting pgACC demonstrated the most favourable clinical outcomes, with a higher proportion of participants exhibiting a clinically meaningful reduction in pain severity [53%; MD (95% CI): - 1.9 (- 2.7, - 1.0)], interference [80%; MD (95% CI): - 2.3 (- 3.5, - 1.2)], and disability [73%; MD (95% CI): - 4.5 (- 6.1, - 2.9)] at 1-month follow-up. ISF-NF training is a feasible, safe, and an acceptable treatment approach for CLBP.

The study of chronic pain continues to generate ever-increasing numbers of publications, but safe and efficacious treatments for chronic pain remain elusive. Recognition of sex-specific mechanisms underlying chronic pain has resulted in a surge of studies that include both sexes. A predominant focus has been on identifying sex differences, yet many newly identified cellular mechanisms and alterations in gene expression are conserved between the sexes. Here we review sex differences and similarities in cellular and molecular signals that drive the generation and resolution of neuropathic pain. The mix of differences and similarities reflects degeneracy in peripheral and central signaling processes by which neurons, immune cells, and glia codependently drive pain hypersensitivity. Recent findings identifying critical signaling nodes foreshadow the development of rationally designed, broadly applicable analgesic strategies. However, the paucity of effective, safe pain treatments compels targeted therapies as well to increase therapeutic options that help reduce the global burden of suffering.

microRNAs (miRNAs) are extracellularly released by cells for intercellular communication, while intracellularly, they inhibit the expression of specific genes. An increasing number of studies suggest that extracellular miRNAs have great potential as both therapeutic targets and disease-specific biomarkers in a variety of diseases, including pain disorders. However, little is known about miRNA release from dorsal root ganglion (DRG) neurons in neuropathic pain caused by peripheral nerve injury. In this study, we investigated the changes in the extracellular release of miRNAs from DRG neurons in a rat model of neuropathic pain induced by chronic constriction injury of the sciatic nerve. We found increased release of six miRNAs (let-7d, miR-21, miR-142-3p, miR-146b, miR-203-3p and miR-221) from primary cultured DRG neurons prepared from rats 7 days after nerve injury. Among these, miR-221 was also increased in serum from days 7 to 28 after nerve injury. In contrast, serum miR-221 levels and its release from DRG neurons were unchanged in an inflammatory pain model produced by intraplantar injection of complete Freund's adjuvant. These results suggest that the increased release of specific miRNAs by DRG neurons may be involved in the pathophysiology of neuropathic pain through extracellular as well as intracellular mechanisms. Furthermore, serum miR-221 may be useful as a biomarker of neuropathic pain caused by peripheral nerve injury.

Neuropathic pain (NP) is often accompanied by sleep disorders, anxiety, depression and other complications, and the pathogenesis is still unclear. Some drugs can relieve patients' pain, but the overall effect is not good. We screened for the key genes related to NP-induced depression based on bioinformatics.

Vascular endothelial barrier disruption is pivotal in the development of acute and chronic pain. Here, we demonstrate a previously unidentified molecular mechanism in which activation of the peripheral Epac1/p-Cav-1 pathway accelerated the disruption of the vascular endothelial barrier, thereby promoting chronic postsurgical pain (CPSP).

The sensory phenotype is believed to provide information about the underlying pathophysiological mechanisms and to be used in the diagnosis and treatment of chronic neuropathic pain. However, the use of standardized quantitative sensory testing (QST) protocols is limited due to high expenditures of time and costs. Thus, a simple bedside-QST battery was recently developed showing good agreement when compared with laboratory QST. The aim of this study was to preliminary validate this bedside-QST protocol.

Dysfunctional top-down pain modulation is a hallmark of fibromyalgia (FM) and physical exercise is a cornerstone in FM treatment. The aim of this study was to explore the effects of a 15-week intervention of strengthening exercises, twice per week, supervised by a physiotherapist, on exercise-induced hypoalgesia (EIH) and cerebral pain processing in FM patients and healthy controls (HC). FM patients (n = 59) and HC (n = 39) who completed the exercise intervention as part of a multicenter study were examined at baseline and following the intervention. Following the exercise intervention, FM patients reported a reduction of pain intensity, fibromyalgia severity and depression. Reduced EIH was seen in FM patients compared to HC at baseline and no improvement of EIH was seen following the 15-week resistance exercise intervention in either group. Furthermore, a subsample (Stockholm site: FM  = 18; HC  = 19) was also examined with functional magnetic resonance imaging (fMRI) during subjectively calibrated thumbnail pressure pain stimulations at baseline and following intervention. A significant main effect of exercise (post > pre) was observed both in FM patients and HC, in pain-related brain activation within left dorsolateral prefrontal cortex and caudate, as well as increased functional connectivity between caudate and occipital lobe bordering cerebellum (driven by the FM patients). In conclusion, the results indicate that 15-week resistance exercise affect pain-related processing within the cortico-striatal-occipital networks (involved in motor control and cognition), rather than directly influencing top-down descending pain inhibition. In alignment with this, exercise-induced hypoalgesia remained unaltered.

Deep brain stimulation (DBS) to treat chronic neuropathic pain has shown variable outcomes. Variations in pain etiologies and DBS targets are considered the main contributing factors, which are, however, underexplored owing to a paucity of patient data in individual studies. An updated meta-analysis to quantitatively assess the influence of these factors on the outcome of DBS for chronic neuropathic pain is warranted, especially considering that the anterior cingulate cortex (ACC) has emerged recently as a new DBS target.

Searching for new compounds with anti-inflammatory properties is a significant target since inflammation is a major cause of pain. A series of pyrazole, imidazopyrazolone, and pyrazolopyrimidine derivatives were designed and synthesized by reaction of 3,5-diamino-1H-pyrazole derivative with cyclic and acyclic carbonyl reagents. The structure of the newly synthesized derivatives were fully characterized using different spectroscopic data and elemental analysis, and therefore, evaluated as COX-2 inhibitors. The in vitro COX-2 activity of the tested derivatives 2-13 displayed moderate to good potency with two derivatives 8 and 13 that exhibiting high potency to COX-2 with IC values of 5.68 ± 0.08 and 3.37 ± 0.07 μM compared with celecoxib (IC = 3.60 ± 0.07 μM) and meloxicam (IC = 7.58 ± 0.13 μM). Furthermore, the most active pyrazolo[1,5-a]pyrimidine derivatives 8 and 13 were evaluated to measure the levels of pro-inflammatory proteins such as TNF-α and IL-6 using qRT-PCR in RAW264.7 cells, and the results showed down-regulation of two immunomodulatory proteins. Surprisingly, these derivatives 8 and 13 revealed a decrease in IL-6 level with inhibition percentages of 65.8 and 70.3%, respectively, compared with celecoxib (% = 76.8). Further, compounds 8 and 13 can regulate and suppress the TNF-α with percentage inhibition of 63.1 and 59.2% to controls, while celecoxib displayed an inhibition percentage of 72.7. The Quantum chemical calculation was conducted, and data explained the structural features crucial to the activity. The molecular docking simulation and ADMET predictions revealed that the most active derivatives have good binding affinity, possess appropriate drug-likeness properties and low toxicity profiles. Finally, compounds 8 and 13 demonstrated COX-2 inhibitors with α-TNF and IL-6 suppression capabilities as a dual-action strategy to get more effective treatment.

Back pain is common among older adults resulting in high societal and economic burden of persistent pain and disability. Pain medications are frequently prescribed for back pain, especially among older patients, but the efficacy of analgesics on back pain in this patient population remains under debate. In the present study, we investigated the outcomes (i.e. pain intensity and disability) of pain medication use in older people with back pain participating in a prospective cohort study.

A meta-analysis was conducted to analyze the incidence of typical and atypical headaches and outcomes following various treatments in patients with Chiari I malformation.

While migraine and cluster headache share some clinical features and therapies, they differ considerably in the frequency and duration of the headache, as well as the inter-attack, or inter-bout, pathophysiology. Neither is fully understood, with their shared pathways being of interest.

The aim of this study was to analyze the effects of ten sessions of active transcranial direct current stimulation transcranial direct current stimulation (tDCS) (2 mA) with 13:20:13 stimulation at M1 in women with fibromyalgia (FM). To the best of our knowledge, this is the first article that uses this protocol in patients with FM. The main hypothesis is that the protocol would be effective in decreasing pain and that the results would last for up to 90 days.

Pain after cancer remains underestimated and undertreated. Precision medicine is a recent concept that refers to the ability to classify patients into subgroups that differ in their susceptibility to, biology, or prognosis of a particular disease, or in their response to a specific treatment, and thus to tailor treatment to the individual patient characteristics. Applying this to pain after cancer, the ability to classify post-cancer pain into the three major pain phenotypes (i.e. nociceptive, neuropathic, and nociplastic pain) and tailor pain treatment accordingly, is an emerging issue. This is especially relevant because available evidence suggests that nociplastic pain is present in an important subgroup of those patients experiencing post-cancer pain. The 2021 International Association for the Study of Pain (IASP) clinical criteria and grading system for nociplastic pain account for the need to identify and correctly classify patients according to the pain phenotype early in their treatment. These criteria are an important step towards precision pain medicine with great potential for the field of clinical oncology. Within this framework, the Cancer Pain Phenotyping (CANPPHE) Network, an international and interdisciplinary group of oncology clinicians and researchers from seven countries, applied the 2021 IASP clinical criteria for nociplastic pain to the growing population of those experiencing post-cancer pain. A manual is provided to allow clinicians to differentiate between predominant nociceptive, neuropathic, or nociplastic pain after cancer. A seven-step diagnostic approach is presented and illustrated using cases to enhance understanding and encourage effective implementation of this approach in clinical practice.

Currently, chemotherapy-induced neuropathic pain (CINP) has limited effective treatment. The roles of Oxytocin (OXT) and the oxytocin receptor (OXTR) in central analgesia have been well documented. However, the expression and function of OXTR in the peripheral nervous system remain unclear. Here, we evaluated the peripheral antinociceptive profiles of OXTR in CINP.

The lymphatic system plays a crucial role in the maintenance of tissue fluid homeostasis and the immunological response to inflammation. Galectin-8 (Gal-8) regulates pathological lymphangiogenesis but the effects of which on inflammation-related condylar bone loss in temporomandibular joint (TMJ) have not been well studied.

Osteoarthritis (OA) is a common musculoskeletal disease that leads to deterioration of articular cartilage, joint pain, and decreased quality of life. When OA develops after a joint injury, it is designated as post-traumatic OA (PTOA). The etiology of PTOA remains poorly understood, but it is known that proteoglycan (PG) loss, cell dysfunction, and cell death in cartilage are among the first signs of the disease. These processes, influenced by biomechanical and inflammatory stimuli, disturb the normal cell-regulated balance between tissue synthesis and degeneration. Previous computational mechanobiological models have not explicitly incorporated the cell-mediated degradation mechanisms triggered by an injury that eventually can lead to tissue-level compositional changes. Here, we developed a 2-D mechanobiological finite element model to predict necrosis, apoptosis following excessive production of reactive oxygen species (ROS), and inflammatory cytokine (interleukin-1)-driven apoptosis in cartilage explant. The resulting PG loss over 30 days was simulated. Biomechanically triggered PG degeneration, associated with cell necrosis, excessive ROS production, and cell apoptosis, was predicted to be localized near a lesion, while interleukin-1 diffusion-driven PG degeneration was manifested more globally. Interestingly, the model also showed proteolytic activity and PG biosynthesis closer to the levels of healthy tissue when pro-inflammatory cytokines were rapidly inhibited or cleared from the culture medium, leading to partial recovery of PG content. The numerical predictions of cell death and PG loss were supported by previous experimental findings. Furthermore, the simulated ROS and inflammation mechanisms had longer-lasting effects (over 3 days) on the PG content than localized necrosis. The mechanobiological model presented here may serve as a numerical tool for assessing early cartilage degeneration mechanisms and the efficacy of interventions to mitigate PTOA progression.

Chronic pain is a prevalent, yet underrecognized, condition in children and adolescents. A biopsychosocial framework has been widely adopted over the past decades and resulted in a new pain classification in the International Classification of Diseases, 11th revision (ICD-11). Nevertheless, little is known about pediatricians' pain concepts.

Sensory processing sensitivity (SPS) describes a genetically influenced trait characterized by greater of information , lower sensory threshold, and ease of overstimulation. It is hypothesized that SPS plays a crucial role in the context of chronic pain. This exploratory study examined SPS as a correlate of pain intensity and pain-related disability in a sample of adolescents reporting chronic pain.

Recent advances in stimulation techniques have improved the efficacy and expanded the applicability of spinal cord stimulation (SCS). Among these techniques, there are no reports on the efficacy of differential target multiplexed (DTM) SCS for chronic postsurgical pain (CPSP) after abdominal surgery. Therefore, we present the successful use of DTM SCS for CPSP after distal pancreatectomy.

Studies have identified demographic, clinical, psychosocial, and perioperative variables associated with persistent pain after a variety of surgeries. This study aimed to perform a systematic review and meta-analysis of factors associated with persistent pain after total knee replacement (TKR) and total hip replacement (THR) surgeries. To meet the inclusion criteria, studies were required to assess variables before or at the time of surgery, include a persistent postsurgical pain (PPSP) outcome measure at least 2 months after a TKR or THR surgery, and include a statistical analysis of the effect of the risk factor(s) on the outcome measure. Outcomes from studies implementing univariate and multivariable statistical models were analyzed separately. Where possible, data from univariate analyses on the same factors were combined in a meta-analysis. Eighty-one studies involving 171,354 patients were included in the review. Because of the heterogeneity of assessment methods, only 44% of the studies allowed meaningful meta-analysis. In meta-analyses, state anxiety (but not trait anxiety) scores and higher depression scores on the Beck Depression Inventory were associated with an increased risk of PPSP after TKR. In the qualitative summary of multivariable analyses, higher preoperative pain scores were associated with PPSP after TKR or THR. This review systematically assessed factors associated with an increased risk of PPSP after TKR and THR and highlights current knowledge gaps that can be addressed by future research.

Dysregulation of sleep heightens pain sensitivity and may contribute to pain chronification. Interventions which consolidate and lengthen sleep have the potential to improve pain control. The main objective of this systematic review was to examine the effects of sleep-promoting pharmacotherapy on pain intensity in patients with chronic pain. Multiple electronic databases were searched from inception to January 2022 to identify relevant randomized controlled trials (RCTs). Two independent reviewers screened titles, abstracts, and full-text articles; extracted data; and assessed risk of bias for each included study. The GRADE approach was used to determine the strength of evidence. The search identified 624 articles. After full-text screening, 10 RCTs (n = 574 randomized participants) involving 3 pharmacologic interventions (melatonin, zopiclone, and eszopiclone) and 7 different chronic pain populations were included. Minimum clinically significant pain reduction ≥30% was reported in 4 studies. There is low-quality evidence (downgraded due to inconsistency and imprecision) that 2 to 8 weeks treatment with a sleep-promoting medication alone or in combination with an analgesic (6 trials, n = 397) decreases pain intensity compared with placebo or the same analgesic treatment alone (SMD -0.58 [95% confidence interval -1.00, -0.17], = 0.006). Analyses of associations between changes in sleep and pain outcomes were only provided in 2 articles, with inconsistent findings. Notably, pain-relieving effects were most consistent in melatonin trials. Only 3 studies implemented polysomnography to obtain objective sleep measures. Low-quality evidence indicates that pharmacologic sleep promotion may decrease pain intensity in chronic pain populations. More research is needed to fully understand the influence of sleep-targeting interventions on pain control.

There has been both great interest in and skepticism about the strategies for headache inhibition in patients with patent foramen ovale and migraines (PFO-migraine). Furthermore, many questions remain about the fundamental pathophysiology of PFO-migraines. Herein, the inhibiting effect of normobaric oxygenation (NBO) on PFO-migraine was analyzed.

Alcohol use disorder (AUD) is a chronic, relapsing disorder characterized by an escalation of drinking and the emergence of negative affective states over time. Within this framework, alcohol may be used in excessive amounts to alleviate withdrawal-related symptoms, such as hyperalgesia. Future effective therapeutics for AUD may need to exhibit the ability to reduce drinking as well as alleviate co-morbid conditions such as pain, as well as take mechanistic sex differences into consideration. Agmatine is an endogenous neuromodulator that has been previously implicated in the regulation of reward and pain processing. In the current set of studies, we examined the ability of agmatine to reduce escalated ethanol drinking in complementary models of AUD where adult male and female mice and rats were made dependent via chronic, intermittent ethanol vapor exposure (CIE). We also examined the ability of agmatine to modify thermal and mechanical sensitivity in alcohol-dependent male and female rats. Agmatine reduced alcohol drinking in a dose-dependent fashion, with somewhat greater selectivity in alcohol-dependent female mice (versus non-dependent female mice) but equivalent efficacy across male mice and both groups of male and female rats. In mice and female rats, this efficacy did not extend to sucrose drinking, indicating some selectivity for ethanol reinforcement. Female rats made dependent on alcohol demonstrated significant hyperalgesia symptoms, and agmatine produced dose-dependent antinociceptive effects across both sexes. While additional mechanistic studies into agmatine are necessary, these findings support the broad-based efficacy of agmatine to treat co-morbid excessive drinking and pain symptoms in the context of AUD.

Previous literature has rarely examined the role of pain in the process of disablement. We investigate how pain associates with disability transitions among older adults, using educational attainment as a moderator. Data are from the National Health and Aging Trends Study, N=6,357; 33,201 one-year transitions between 2010-2020. We estimate multinomial logistic models predicting incidence or onset of and recovery from functional limitation and disability. Results show pain significantly predicts functional limitation and disability onset one year after a baseline observation, and decreases odds of recovery from functional limitation or disability. Contrary to expectations, higher education does not buffer the association of pain in onset of disability, but supporting expectations, it facilitates recovery from functional limitation or disability among those with pain. The analysis implicates pain as having a key role in the disablement process and suggests that education may moderate this with respect to coping with and subsequently recovering from disability.

Central post-stroke pain (CPSP) is a type of central neuropathic pain, whose underlying mechanisms remain unknown. We previously reported that bilateral carotid artery occlusion (BCAO)-induced CPSP model mice showed mechanical hypersensitivity and decreased mRNA levels of preproorexin, an orexin precursor, in the hypothalamus. Recently, nicotine was shown to regulate the neuronal activity of orexin in the lateral hypothalamus (LH) and suppress inflammatory and neuropathic pain. In this study, we evaluated whether nicotine could suppress BCAO-induced mechanical allodynia through the activation of orexinergic neurons. Mice were subjected to BCAO for 30 min. Mechanical hypersensitivity was assessed by the von Frey test. BCAO mice showed hypersensitivity to mechanical stimuli three days after BCAO surgery. The intracerebroventricular injection of nicotine suppressed BCAO-induced mechanical hypersensitivity in a dose-dependent manner. These effects were inhibited by α7 or α4β2-nicotinic receptor antagonists. After nicotine injection, the level of c-fos, a neuronal activity marker, increased in the LH and locus coeruleus (LC) of Sham and BCAO mice. Increased number of c-Fos-positive cells partly colocalized with orexin A-positive cells in the LH, as well as tyrosine hydroxylase-positive cells in the LC. Orexinergic neurons project to the LC area. Nicotine-induced antinociception tended to cancel by the pretreatment of SB334867, an orexin receptor1 antagonist into the LC. Intra-LH microinjection of nicotine attenuated BCAO-induced mechanical hypersensitivity. Nicotine-induced antinociception was inhibited by intrathecal pre-treatment with yohimbine, an α2 adrenergic receptor antagonist. These results indicated that nicotine may suppress BCAO-induced mechanical hypersensitivity through the activation of the descending pain control system via orexin neurons.

Itch occurs in various dermatologic and systemic conditions. Many patients report that certain foods instigate itch, although there is limited published information in dermatology on food-induced pruritus. In addition, itch severity is rarely mentioned. Food can induce pruritus through either ingestion or direct contact with skin or mucosal membranes. The most common type of itch provoked by food is acute urticaria, often through the classical immunoglobulin E (IgE)-mediated pathway. Other mechanisms include non-IgE-mediated, mixed (IgE-mediated and non-IgE-mediated), T-cell-mediated, and nonimmune reactions. For patients presenting with urticaria, generalized pruritus, oral pruritus, or dermatitis, a thorough history is warranted, and possible food associations should be considered and assessed. Although any food seems to have the potential to elicit an immune response, certain foods are especially immunogenic. Treatment includes avoidance of the trigger and symptom management. Careful consideration should be used as to avoid unnecessarily restrictive elimination diets.

Sleep disturbance (SD) is common in atopic dermatitis (AD). We examined the longitudinal course of SD and relationship with itch in AD patients. A prospective, dermatology practice-based study was performed (N = 1295) where patients were assessed at baseline and follow-up visits. At baseline, 16.9% of the patients had severe SD based on Patient-Reported Outcomes Information System (PROMIS) SD scores, 19.1% had difficulty falling asleep, 22.9% had difficulty staying asleep, and 34.2% had SD from AD. A total of 31.4% of the patients with difficulty staying asleep at baseline experienced persistent difficulties (for 3 follow-ups or more). Only 17.7% with baseline difficulty falling asleep had persistent disturbance. Despite significant fluctuation in sleep scores, SD generally improved over time. Of the patients facing baseline SD from AD, 31.5% experienced SD at the first visit, and only 12.3% experienced persistent SD at the second follow-up visit. Predictors of increased PROMIS sleep-related impairment scores over time included baseline PROMIS sleep-related impairment scores (0.74 [0.68-0.80]), having 3 to 6 nights of itch (2.22 [0.85-3.59]), and severe/very severe AD (4.40 [2.60-6.20]). A significant proportion of adult AD patients, particularly those with moderate-severe AD and frequent itch, had baseline SD. Although sleep scores generally improved over time, many patients experienced a fluctuating or persistent course.

We hypothesized that the response of trigeminal dermal blood flow (DBF) in the trigeminal system and consecutive expansion of flare response to capsaicin would differ from the somatosensory system (arm). We also investigated whether there are differences between patients with migraine and healthy controls (HC).

Neuralgia, or nerve pain, is a common presenting complaint for the hand surgeon. When the nerve at play is easily localized, and the cause of the pain is clear (eg, carpal tunnel syndrome), the patient may be easily treated with excellent results. However, in more complex cases, the underlying pathophysiology and cause of neuralgia can be more difficult to interpret; if incorrectly managed, this leads to frustration for both the patient and surgeon. Here we offer a way to conceptualize neuralgia into 4 categories-compression neuropathy, neuroma, painful hyperalgesia, and phantom nerve pain-and offer an illustrative clinical vignette and strategies for optimal management of each. Further, we delineate the reasons why compression neuropathy and neuroma are amenable to surgery, while painful hyperalgesia and phantom nerve pain are not.

Continuing professional development is an important means of improving access to effective patient care. Although pain content has increased significantly in prelicensure programs, little is known about how postlicensure health professionals advance or maintain competence in pain management.

In this study, we pursue determining the effect of pentoxifylline (Ptx) in delayed-onset muscle soreness (DOMS) triggered by exposing untrained mice to intense acute swimming exercise (120 min), which, to our knowledge, has not been investigated. Ptx treatment (1.5, 4.5, and 13.5 mg/kg; i.p., 30 min before and 12 h after the session) reduced intense acute swimming-induced mechanical hyperalgesia in a dose-dependent manner. The selected dose of Ptx (4.5 mg/kg) inhibited recruitment of neutrophils to the muscle tissue, oxidative stress, and both pro- and anti-inflammatory cytokine production in the soleus muscle and spinal cord. Furthermore, Ptx treatment also reduced spinal cord glial cell activation. In conclusion, Ptx reduces pain by targeting peripheral and spinal cord mechanisms of DOMS.

Calcitonin gene-related peptide-targeted drugs have proven safe and effective for migraine prevention in large randomized-controlled, double-blind trials with an average duration of six months. Open-label studies may provide additional information on the long-term safety and efficacy of these substances.

The aversive aspect of pain constitutes a major burden faced by pain patients. This has been recognized by the pain research community, leading to the development of novel methods focusing on affective-motivational behaviour in pain model animals. The most common tests used to assess pain aversion in animals require cognitive processes, such as associative learning, complicating the interpretation of results. To overcome this issue, studies in recent years have utilized unconditioned escape as a measure of aversion. However, the vast majority of these studies quantify jumping – a common escape behaviour in mice, but not in adult rats, thus limiting its use. Here, we present the "Heat Escape Threshold" (HET) paradigm for assessing heat aversion in rats. We demonstrate that this method can robustly and reproducibly detect the localized effects of an inflammatory pain model (intraplantar carrageenan) in male and female Sprague-Dawley rats. In males, a temperature that evoked unconditioned escape following carrageenan treatment also induced real-time place avoidance (RTPA). Systemic morphine more potently alleviated carrageenan-induced heat aversion (as measured by the HET and RTPA methods), as compared to reflexive responses to heat (as measured by the Hargreaves test), supporting previous findings. Next, we examined how blocking of excitatory transmission to the lateral parabrachial nucleus (LPBN), a key node in the ascending pain system, affects pain behaviour. Using the HET and Hargreaves tests, we show that intra-LPBN application of glutamate antagonists reverses the effects of carrageenan on both affective and reflexive pain behaviour, respectively. Finally, we employed the HET paradigm in a generalized opioid-withdrawal pain model. Withdrawal from a brief systemic administration of remifentanil resulted in a long-lasting and robust increase in heat aversion, but no change in reflexive responses to heat. Taken together, these data demonstrate the utility of the HET paradigm as a novel tool in preclinical pain research.

In this study, Brillouin and Raman micro-Spectroscopy (BRamS) and Machine Learning were used to set-up a new diagnostic tool for Osteoarthritis (OA), potentially extendible to other musculoskeletal diseases. OA is a degenerative pathology, causing the onset of chronic pain due to cartilage disruption. Despite this, it is often diagnosed late and the radiological assessment during the routine examination may fail to recognize the threshold beyond which pharmacological treatment is no longer sufficient and prosthetic replacement is required. Here, femoral head resections of OA-affected patients were analyzed by BRamS, looking for distinctive mechanical and chemical markers of the progressive degeneration degree, and the result was compared to standard assignment via histological staining. The procedure was optimized for diagnostic prediction by using a machine learning algorithm and reducing the time required for measurements, paving the way for possible future in vivo characterization of the articular surface through endoscopic probes during arthroscopy.

Attention-deficit/hyperactivity disorder (ADHD) has been reported to be associated with primary chronic pain syndromes, such as fibromyalgia, migraine, and chronic low back pain. Although idiopathic orofacial pain (IOP) is classified as burning mouth syndrome or persistent idiopathic facial or dentoalveolar pain and as a primary chronic pain, the association between IOP and ADHD has not been investigated. This retrospective cohort study investigated the severity of ADHD symptoms measured using the ADHD scale and the effects of treatment using ADHD drugs and the dopamine system stabilizer aripiprazole. The participants were 25 consecutive patients with refractory IOP referred to a psychiatrist and diagnosed with coexisting ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-5. The ADHD scale scores were higher in patients with intractable IOP than those in the general population. Pharmacotherapy used in this study led to clinically significant improvements in pain, anxiety/depression, and pain catastrophizing. Intractable IOP and ADHD were shown to be associated. In the future, screening and pharmacotherapy for ADHD should be considered in the treatment of intractable IOP.

Intervertebral disc degeneration (IVDD) mainly manifests as an imbalance between the synthesis and degradation of cellular and extracellular matrix (ECM) components. The cytokine interleukin (IL)-1β-induced inflammatory response of intervertebral discs causes ECM degradation. The aim of this study was to investigate the effects of a 970-nm diode laser therapy (DLT) on inflammatory cytokine IL-1β and ECM degradation proteinases in nucleus pulposus (NP) tissues in a puncture-induced rabbit IVDD model. Thirty-six New Zealand white rabbits were randomly divided into six groups: the normal group, IVDD group, laser group, sham laser group, IVDD + anisomycin (p38MAPK signaling pathway agonist), and laser + anisomycin group. Effects of laser on IVDD progression were detected using radiographic and magnetic resonance imaging. Hematoxylin and eosin, Alcian blue, safranin O-fast green staining, western blotting, and immunohistochemistry staining were performed for the histological analysis and molecular mechanism underlying protection against puncture-induced matrix degradation in NP tissues by DLT. DLT reduced the degree of disc degeneration in the gross anatomy of the disc and increased the T2-weighted signal intensity of NP. Inflammatory cytokine IL-1β levels in the disc were significantly reduced after DLT suppressed the matrix-degrading proteinases MMP13 and ADAMTS-5 and upregulated the protein expression of collagen II and aggrecan. Moreover, it inhibited the p38MAPK signaling pathway in NP tissues in a puncture-induced rabbit IVDD model. DLT reduced puncture-induced overexpression of inflammatory cytokines, mainly IL-1β, thus inhibiting matrix degeneration of NP tissues and ameliorating IVDD. This may be related to inhibition of the p38 MAPK signaling pathway.

Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent Nav1.8-positive nociceptive cold sensors have been shown to be unmasked by oxaliplatin, and this event has been causally linked to the development of cold allodynia. We examined the effects of pregabalin on oxaliplatin-evoked unmasking of cold sensitive neurons using mice expressing GCaMP-3 in all sensory neurons. Intravenous injection of pregabalin significantly ameliorates cold allodynia, while decreasing the number of cold sensitive neurons by altering their excitability and temperature thresholds. The silenced neurons are predominantly medium/large mechano-cold sensitive neurons, corresponding to the 'silent' cold sensors activated during neuropathy. Deletion of α2δ1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neurons. Thus, these results define a novel, peripheral inhibitory effect of pregabalin on the excitability of 'silent' cold-sensing neurons in a model of oxaliplatin-dependent cold allodynia.Pregabalin is an analgesic drug in the clinic, that is supposed to act by blocking neurotransmitter release. Here we show that silent nociceptors that are activated by chemotherapeutic insults like oxaliplatin are silenced by pregabalin, which blocks the associated pain. This mode of action suggests that peripheral acting pregabalin-like drugs could be very useful for pain during chemotherapy, as they would have no CNS side effects – a problem for many patients with pregabalin. This novel effect of pregabalin is mediated by its interaction with the α2δ1 calcium channel subunit, but how this works is not yet understood.

To compare two agents that can induce a rat model of temporomandibular joint osteoarthritis (TMJOA) by chemical induction: monosodium iodoacetate (MIA) and collagenase type 2 (Col-2). We wished to ascertain the best agent for assessing drug-delivery systems (DDSs).

Aging is a risk factor for several debilitating conditions including those related to chronic back pain and intervertebral disc degeneration, both of which have no cure. Mouse models are useful tools for studying disc degeneration and chronic back pain in a tightly controlled and clinically relevant aging environment. Moreover, mice offer the advantage of carrying out longitudinal studies to understand the etiology and progression of disc pathology induced by genetic or surgical strategies. Previously, age-related behavioral trends of discomfort and enhanced nociception in mice were reported; however, whether these measures are mediated by structural and pathological changes in the disc is unknown.

Spinal cord injury (SCI) in humans frequently causes intractable chronic pain. Females are susceptible to worsened pain compared to males, and females may show higher pain prevalence after SCI. Despite this difference in clinical prevalence of SCI pain, few preclinical studies have systematically studied in rodents sex differences in SCI-elicited pain-related behaviors. Here, we leverage data from a large cohort of mice to test whether contusion SCI consistently causes pain symptoms in mice, and to establish whether female (vs. male) mice display heightened hypersensitivity after SCI. Mechanical and heat sensory thresholds were assessed using the von Frey test and Hargreaves test, respectively. In an initial experiment, female mice receiving moderate 60 kDyn SCI or moderate-to-severe 75 kDyn SCI at T9 both exhibited mechanical and heat pain symptoms compared to sham controls. 75 kDyn SCI caused excess motor deficits that confounded defining pain sensitivity at acute times, so the moderate SCI force was used for subsequent experiments. Next, adult female and male C57BL6/J mice received sham surgery or T9 moderate contusion SCI. Comparing female to male mice after SCI, we reveal that mice of both sexes displayed mechanical and heat hypersensitivity compared to sham controls, from acute-to-chronic post-injury times. Females had amplified SCI-elicited hypersensitivity compared to males. Our data suggest that thoracic contusion SCI elicits consistent and persistent pain-associated symptoms, which are more intense in female vs. male mice. These results have important implications for uncovering sex-specific mechanisms and therapeutic targets to ameliorate neuropathic pain after SCI.

Ferroptosis is an inflammatory programmed cell death process that is dependent on iron deposition and lipid peroxidation. The P2X7 receptor not only is involved in the pain process but also is closely related to the onset of depression. Gallic acid (3,4,5-trihydroxybenzoic acid), which is naturally found in a variety of plants, exhibits anti-inflammatory, antioxidant, and analgesic effects. This study established a rat model with the comorbidity of chronic constrictive injury (CCI) plus chronic unpredictable mild stress (CUMS) to explore the role and mechanism of gallic acid in the treatment of pain and depression comorbidity. Our experimental results showed that pain and depression-like behaviors were more obvious in the chronic constriction injury (CCI) plus chronic unpredictable mild stimulation (CUMS) group than they were in the sham operation group, and the P2X7-reactive oxygen species (ROS) signaling pathway was activated. The tissue iron concentration was increased, and mitochondrial damage was observed in the CCI plus CUMS group. These results were alleviated with gallic acid treatment. Therefore, we speculate that gallic acid inhibits the ferroptosis of the spinal microglia by regulating the P2X7-ROS signaling pathway and relieves the behavioral changes in rats with comorbid pain and depression.

Placebo effects, positive treatment outcomes that go beyond treatment processes, can alter sensations through learning mechanisms. Understanding how methodological factors contribute to the magnitude of placebo effects will help define the mechanisms by which these effects occur. We conducted a systematic review and meta-analysis of experimental placebo studies in cutaneous pain and itch in healthy samples, focused on how differences in methodology contribute to the resulting placebo effect magnitude. We conducted meta-analyses by learning mechanism and sensation, namely, for classical conditioning with verbal suggestion, verbal suggestion alone, and observational learning, separately for pain and itch. We conducted subgroup analyses and meta-regression on the type of sensory stimuli, placebo treatment, number of acquisition and evocation trials, differences in calibrated intensities for placebo and control stimuli during acquisition, age, and sex. We replicated findings showing that a combination of classical conditioning with verbal suggestion induced larger placebo effects on pain (k = 68, g = 0.59) than verbal suggestion alone (k = 39, g = 0.38) and found a smaller effect for itch with verbal suggestion alone (k = 7, g = 0.14). Using sham electrodes as placebo treatments corresponded with larger placebo effects on pain than when topical gels were used. Other methodological and demographic factors did not significantly affect placebo magnitudes. Placebo effects on pain and itch reliably occur in experimental settings with varied methods, and conditioning with verbal suggestion produced the strongest effects. Although methods may shape the placebo effect to some extent, these effects appear robust overall, and their underlying learning mechanisms may be harnessed for applications outside the laboratory.

Scorpion sting envenomations (SSE) are feared by the intense pain that they produce in victims. Pain from SSE is triggered mainly by the presence of neurotoxins in the scorpion venom that modulates voltage-gated ion channels. In Brazil, SSE is mostly caused by Tityus serrulatus, popularly known as yellow scorpion. Here, we evaluated experimental spontaneous nociception induced by T. serrulatus venom as well as its isolated neurotoxins Ts1, Ts5, Ts6, Ts8, and Ts19 frag II, evidencing different degrees of pain behavior in mice. In addition, we developed a mice-derived polyclonal antibody targeting Ts5 able to neutralize the effect of this neurotoxin, showing that Ts5 presents epitopes capable of activating the immune response, which decreased considerably the nociception produced by the whole venom. This is the pioneer study to explore nociception using different classes of T. serrulatus neurotoxins on nociception (α-NaTx, β-NaTx, α-KTx, and β-KTx), targeting potassium and sodium voltage-gated channels, besides demonstrating that Ts5 plays an important role in the scorpion sting induced-pain.

Chronic low back pain (cLBP) afflicts 8. 2% of adults in the United States, and is the leading global cause of disability. Neuropsychiatric co-morbidities including anxiety, depression, and substance abuse- are common in cLBP patients. In particular, cLBP is a risk factor for opioid addiction, as more than 50% of opioid prescriptions in the United States are for cLBP. Misuse of these prescriptions is a common precursor to addiction. While associations between cLBP and neuropsychiatric disorders are well established, causal relationships for the most part are unknown. Developing effective treatments for cLBP, and associated co-morbidities, requires identifying and understanding causal relationships. Rigorous methods for causal inference, a process for quantifying causal effects from observational data, have been developed over the past 30 years. In this review we first discuss the conceptual model of cLBP that current treatments are based on, and how gaps in causal knowledge contribute to poor clinical outcomes. We then present cLBP as a "Big Data" problem and identify how advanced analytic techniques may close knowledge gaps and improve clinical outcomes. We will focus on causal discovery, which is a data-driven method that uses artificial intelligence (AI) and high dimensional datasets to identify causal structures, discussing both constraint-based (PC and Fast Causal Inference) and score-based (Fast Greedy Equivalent Search) algorithms.

An acute bout of exercise typically leads to short term exercise induced hypoalgesia (EIH), but this response is more variable in many chronic pain populations, including knee osteoarthritis (OA) and fibromyalgia (FM). There is evidence of autonomic nervous system (ANS) dysfunction in some chronic pain populations that may contribute to impaired EIH, but this has not been investigated in people with knee OA. The aim of this study was to assess the acute effects of isometric exercise on the nociceptive and autonomic nervous systems in people with knee OA and FM, compared to pain-free controls.

Electrical stimulation of skin nociceptors is gaining attention in pain research and peripheral neuropathy diagnosis. However, the optimal parameters for selective stimulation are still difficult to determine because they require simultaneous characterization of the electrical response of small fibers (Aδ- and C-fibers). In this study, we measured the electrical threshold responses of small fibers to train-pulse stimulation in humans for the first time. We also examined selective stimulation a computational model, which combines electrical analysis, and terminal fiber and synaptic models, including the first cutaneous pain C-fiber model. Selective stimulation of small fibers is performed by injecting train-pulse stimulation coaxial electrodes with an intraepidermal needle tip at varying pulse counts and frequencies. The activation Aδ- or C-fibers was discriminated from the differences in reaction time. Aδ-fiber elicited a pinpricking sensation with a mean reaction time of 0.522 s, and C-fiber elicited a tingling sensation or slight burning itch with a mean reaction time of 1.243 s. The implemented multiscale electrical model investigates synaptic effects while considering stimulation waveform characteristics. Experimental results showed that perception thresholds decreased with the number of consecutive pulses and frequency up to convergence (five pulses or 70 Hz) during the selective stimulation of Aδ- and C-fibers. Considering the synaptic properties, the optimal stimulus conditions for selective stimulation of Aδ- vs. C-fibers were train of at least four pulses and a frequency of 40-70 Hz at a pulse width of 1 ms. The experimental results were modeled with high fidelity by incorporating temporal synaptic effects into the computational model. Numerical analysis revealed terminal axon thickness to be the most important biophysical factor affecting threshold variability. The computational model can be used to estimate perception thresholds while understanding the mechanisms underlying the selective stimulation of small fibers. The parameters derived here are important in exploring selective stimulation between Aδ- and C-fibers for diagnosing neuropathies.

After finishing cancer treatment, breast cancer survivors often experience both physical and psychosocial symptoms such as pain. In some, pain can persist for months or even years. Pain is a complex experience. Its occurrence and maintenance are explained through interactions between multiple factors, which are biological/physiological, psychological, and social in nature. Unaddressed needs related to this problem – such as insufficient pain relief, limited validation of the problem, and minimal physical and psychological support – may cause severe disability and negatively impact well-being and quality of life. This study investigated how breast cancer survivors perceive their (chronic) pain complaints to be addressed during follow-up care. Furthermore, we explored how they coped with the way their trajectories happened to unfold.

Chronic pain remains a significant burden worldwide while treatments are often limited by safety or efficacy. The decarboxylated form of L-arginine, agmatine, antagonizes N-methyl-D-aspartate receptors, inhibits nitric oxide synthase, and reverses behavioral neuroplasticity. We hypothesized that expressing the proposed synthetic enzyme for agmatine in the sensory pathway could reduce chronic pain without motor deficits. Intrathecal delivery of an adeno-associated viral vector carrying the gene for arginine decarboxylase prevented the development of chronic neuropathic pain as induced by spared nerve injury in mice and rats and persistently reversed established hypersensitivity 266 days post-injury. Spinal long-term potentiation was inhibited by both exogenous agmatine and AAV-hADC vector pre-treatment but was enhanced in rats treated with anti-agmatine immunoneutralizing antibodies. These data suggest that endogenous agmatine modulates the neuroplasticity associated with chronic pain. Development of approaches to access this inhibitory control of neuroplasticity associated with chronic pain may yield important non-opioid pain-relieving options.

Calcium ion movements between cellular stores and the cytosol govern muscle contraction, the most energy-consuming function in mammals, which confers skeletal myofibers a pivotal role in glycemia regulation. Chronic myoplasmic calcium elevation ("calcium stress"), found in malignant hyperthermia-susceptible (MHS) patients and multiple myopathies, has been suggested to underlie the progression from hyperglycemia to insulin resistance. What drives such progression remains elusive. We find that muscle cells derived from MHS patients have increased content of an activated fragment of GSK3β – a specialized kinase that inhibits glycogen synthase, impairing glucose utilization and delineating a path to hyperglycemia. We also find decreased content of junctophilin1, an essential structural protein that colocalizes in the couplon with the voltage-sensing Ca1.1, the calcium channel RyR1 and calpain1, accompanied by an increase in a 44 kDa junctophilin1 fragment (JPh44) that moves into nuclei. We trace these changes to activated proteolysis by calpain1, secondary to increased myoplasmic calcium. We demonstrate that a JPh44-like construct induces transcriptional changes predictive of increased glucose utilization in myoblasts, including less transcription and translation of GSK3β and decreased transcription of proteins that reduce utilization of glucose. These effects reveal a stress-adaptive response, mediated by the novel regulator of transcription JPh44.

The primary objective of this paper is to (1) provide a summary of human studies that have used brain derived neurotrophic factor (BDNF) as a biomarker, (2) review animal studies that help to elucidate the mechanistic involvement of BDNF in the development and maintenance of neuropathic pain (NP), and (3) provide a critique of the existing measurement techniques to highlight the limitations of the methods utilized to quantify BDNF in different biofluids in the blood (i.e., serum and plasma) with the intention of presenting a case for the most reliable and valid technique. Lastly, this review also explores potential moderators that can influence the measurement of BDNF and provides recommendations to standardize its quantification to reduce the inconsistencies across studies.

Despite extensive study, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain after corneal refractive surgery provides a model, in humans, of the effect of injury to trigeminal afferent nerves. Axons of trigeminal ganglion neurons that innervate the cornea are transected by laser assisted in situ keratomileusis (LASIK). While most patients do not experience post-operative pain, a small subgroup develop persistent ocular pain. We previously carried out genomic analysis and determined that some patients with persistent pain after axotomy of corneal axons during refractive surgery carry mutations in genes that encode the electrogenisome of trigeminal ganglion neurons – the ensemble of ion channels and receptors that regulate excitability within these cells -including SCN9A, which encodes sodium channel Nav1.7, a threshold channel abundantly expressed in sensory neurons, that has been implicated in a number of pain-related disorders. Here, we describe the biophysical and electrophysiological profiling of the P610T-Nav1.7 mutation found in two male siblings with persistent ocular pain after refractive surgery. Our results indicate that this mutation impairs the slow inactivation of Nav1.7. As expected from this pro-excitatory change in channel function, we also demonstrate that this mutation produces hyperexcitability in trigeminal ganglion neurons. These findings suggest that this gain-of-function mutation in Nav1.7 may contribute to pain after injury to the axons of trigeminal ganglion neurons.

One aim of the Back Pain Consortium (BACPAC) Research Program is to develop an integrated model of chronic low back pain that is informed by combined data from translational research and clinical trials. We describe efforts to maximize data harmonization and accessibility to facilitate Consortium-wide analyses.

There are indications that use of menopausal hormone therapy (MHT) and oral contraceptives (OC) increases the risk of low back pain (LBP), with higher oestrogen levels involved in the underlying mechanisms. The purpose of the present study was to investigate associations between use of systemic MHT or OC and risk of chronic LBP in a large population-based data set.

Up to a quarter of the world's population experience chronic pain, which, in addition to interfering with daily activities and waking function, is often associated with poor sleep. Individuals experiencing poor sleep are often encouraged to implement sleep hygiene strategies. However, current sleep hygiene strategies have not been developed considering the unique challenges faced by individuals with chronic pain and therefore they might not be as effective in this population. The aim of this scoping review is to map the state of the existing literature examining sleep hygiene strategies in individuals with chronic pain.

The development of restless legs syndrome (RLS) has been rarely reported during and following opioid withdrawal. We aimed to determine the presence and severity of RLS symptoms during and after supervised opioid tapering.

Chronic pain and opioid use disorder (OUD) individually represent a risk to health and well-being. Concerningly, there is evidence that they are frequently co-morbid. While few treatments exist that simultaneously target both conditions, preliminary work has supported the feasibility of an integrated behavioral treatment targeting pain interference and opioid misuse. This treatment combined Acceptance and Commitment Therapy (ACT) and Mindfulness-Based Relapse Prevention (ACT+MBRP). This paper describes the protocol for the adequately powered efficacy study of this integrated treatment.

Migraine is a neurological disease that has several physical and psychological complications, which is characterized by disability and impaired quality of life.

To systematically evaluate the effectiveness and potential underlying mechanisms of acupuncture in the treatment of experimental model of migraine in rats.

The objective of this study was to assess women's healthcare providers' treatment practices for pregnant women with migraine.

The understanding of inflammation in osteoarthritis is rapidly evolving. This review highlights important basic science, mechanistic, and clinical findings since 2020 that underscore the current notion of osteoarthritis as an inflammatory disease.

Post-stroke pain (PSP) is a common complication after stroke and affects patients' quality of life. Currently, drug therapy and non-invasive brain stimulation are common treatments for PSP. Given the poor efficacy of drug therapy and various side effects, non-invasive brain stimulation, such as repetitive transcranial magnetic stimulation (rTMS), has been accepted by many patients and attracted the attention of many researchers because of its non-invasive and painless nature. This article reviews the therapeutic effect of rTMS on PSP and discusses the possible mechanisms. In general, rTMS has a good therapeutic effect on PSP. Possible mechanisms of its analgesia include altering cortical excitability and synaptic plasticity, modulating the release of related neurotransmitters, and affecting the structural and functional connectivity of brain regions involved in pain processing and modulation. At present, studies on the mechanism of rTMS in the treatment of PSP are lacking, so we hope this review can provide a theoretical basis for future mechanism studies.

Chronic orofacial pain is a common and incompletely defined clinical condition. The role of G protein-coupled estrogen receptor 1 (GPER1) as a new estrogen receptor in trunk and visceral pain regulation is well known. Here, we researched the role of GPER1 in the rostral ventral medulla (RVM) during chronic orofacial pain.

Low back pain (LBP) is a common biopsychosocial health problem. Meditation may provide a complementary treatment option for LBP patients.

This study aimed to investigate changes in dynamic functional network connectivity (FNC) in patients with vestibular migraine (VM) and explore their relationship with clinical manifestations.

Chronic neuropathic pain (NP) is a chronic pain condition that severely impacts a patient's life. Pain management has proved to be inefficient due to a lack of a simple clinical tool that may identify and monitor NP. A low-cost, noninvasive tool that provides relevant information on NP is the electroencephalogram (EEG). However, the commonly used linear EEG features have proved to be limited in characterizing NP pathophysiology. This study sought to determine whether nonlinear EEG features such as approximate entropy (ApEn) would better differentiate pain severity than absolute band power.

To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease.

To investigate whether sensory sensitivity is associated with the perceived severity of Visual Snow Syndrome (VSS) symptoms.

It is documented that some of the opioids prescribed to manage chronic pain are diverted and used for nonmedical purposes. We investigated whether a skill-based, chronic pain management (CPM) educational program could improve first-year family medicine residents' comfort, knowledge, and concerns in assessing and managing patients who use opioids for chronic noncancer pain.

Microglia have been identified for a century. In this period, their ontogeny and functions have come to light thanks to the tireless efforts of scientists. However, numerous documents are being produced, making it challenging for scholars, especially those new to the field, to understand them thoroughly. Therefore, having a reliable method for quickly grasping a field is crucial.

Dysmenorrhea is suggested to increase the risk of chronic pain by enhancing central sensitization. However, little is known about whether emotional and cognitive responses induced by dysmenorrhea contribute to chronic pain interference. This study examined the association between catastrophizing specific to dysmenorrhea and both dysmenorrhea and chronic pelvic pain (CPP)-associated pain interference.

In this study, we used proton Magnetic Resonance Spectroscopy (1H-MRS) to determine the neuronal function in the thalamus and primary somatosensory (S1) cortex in different subgroups of DPN, including subclinical- and painful-DPN.

Personalised and targeted interventions have revolutionised cancer treatment and dramatically improved survival rates in recent decades. Nonetheless, effective pain management remains a problem for patients diagnosed with cancer, who continue to suffer from the painful side effects of cancer itself, as well as treatments for the disease. This problem of cancer pain will continue to grow with an ageing population and the rapid advent of more effective therapeutics to treat the disease. Current pain management guidelines from the World Health Organisation are generalised for different pain severities, but fail to address the heterogeneity of mechanisms in patients with varying cancer types, stages of disease and treatment plans. Pain is the most common complaint leading to emergency unit visits by patients with cancer and over one-third of patients that have been diagnosed with cancer will experience under-treated pain. This review summarises preclinical models of cancer pain states, with a particular focus on cancer-induced bone pain and chemotherapy-associated pain. We provide an overview of how preclinical models can recapitulate aspects of pain and sensory dysfunction that is observed in patients with persistent cancer-induced bone pain or neuropathic pain following chemotherapy. Peripheral and central nervous system mechanisms of cancer pain are discussed, along with key cellular and molecular mediators that have been highlighted in animal models of cancer pain. These include interactions between neuronal cells, cancer cells and non-neuronal cells in the tumour microenvironment. Therapeutic targets beyond opioid-based management are reviewed for the treatment of cancer pain.

To assess the benefits and harms of cannabinoids in participants with pain.

Osteoarthritis (OA) causes joint pain, stiffness, and dysfunction in middle-aged and older adults; however, its pathogenesis remains unclear. Circular RNAs (circRNAs) are differentially expressed in patients with OA and participate in a multigene, multitarget regulatory network. CircRNAs are involved in the development of OA through inflammatory responses, including proliferation, apoptosis, autophagy, differentiation, oxidative stress, and mechanical stress. Most circRNAs are used as intracellular miRNA sponges in chondrocytes, endplate chondrocytes, mesenchymal stem cells, synoviocytes, and macrophages to promote the progression of OA. However, a small portion of circRNAs participates in the pathogenesis of OA by intracellular mechanisms, such as protein binding, methylation, or intercellular exosome pathways. In this sense, circRNAs might serve as potential novel biomarkers and therapeutic targets for OA.

Itch is an unpleasant sensation followed by an intense desire to scratch. Previous researches have advanced our understanding about the role of anterior cingulate cortex and prelimbic cortex in itch modulation, whereas little is known about the effects of retrosplenial cortex (RSC) during this process. Here we firstly confirmed that the neuronal activity of dysgranular RSC (RSCd) is significantly elevated during itch-scratching processing through c-Fos immunohistochemistry and fiber photometry recording. Then with designer receptors exclusively activated by designer drugs approaches, we found that pharmacogenetic inhibition of global RSCd neurons attenuated the number of scratching bouts as well as the cumulative duration of scratching bouts elicited by both 5-HT or compound 48/80 injection into rats' nape or cheek; selective inhibition of the pyramidal neurons in RSCd, or of the excitatory projections from caudal anterior cingulate cortex (cACC) to RSCd, demonstrated the similar effects of decreasing itch-related scratching induced by both 5-HT or compound 48/80. Pharmacogenetic intervention of the neuronal or circuitry activities did not affect rats' motor ability. This study presents direct evidence that pyramidal neurons in RSCd, and the excitatory projection from cACC to RSCd are critically involved in central regulation of both histaminergic and nonhistaminergic itch.

Pain-induced gamma-band oscillations (GBOs) are one of the most promising biomarkers of the pain experience. Although GBOs reliably encode pain perception across different individuals and species, considerable heterogeneity could be observed in the characteristics and functions of GBOs. However, such heterogeneity of GBOs and its underlying sources have rarely been detailed previously. Here, we conducted a systematic review and meta-analysis to characterize the temporal, frequential, and spatial characteristics of GBOs and summarize the functional significance of distinct GBOs. We found that GBOs heterogeneity was mainly related to pain types, with a higher frequency (~66Hz) GBOs at the sensorimotor cortex elicited by phasic pain and a lower frequency (~55Hz) GBOs at the prefrontal cortex associated with tonic and chronic pains. Positive correlations between GBO magnitudes and pain intensity were mainly observed in healthy participants. Notably, the characteristics and functions of GBOs seem to be phylogenetically conserved across humans and rodents. Altogether, we provide a comprehensive description of heterogeneous GBOs in pain and nociception, laying the foundation for clinical applications of GBOs.

Opioids are excellent analgesics for the clinical treatment of various types of acute and chronic pain, particularly cancer-related pain. Nevertheless, it is well known that opioids have some nasty side effects, including immunosuppression, which is commonly overlooked. As a result, the incidence of opportunistic bacterial and viral infections increases in patients with long-term opioid use. Nowadays, there are no effective medications to alleviate opioid-induced immunosuppression. Understanding the underlying molecular mechanism of opioids in immunosuppression can enable researchers to devise effective therapeutic interventions. This review comprehensively summarized the exogenous opioids-induced immunosuppressive effects and their underlying mechanisms, the regulatory roles of endogenous opioids on the immune system, the potential link between opioid immunosuppressive effect and the function of the central nervous system (CNS), and the future perspectives in this field.

Chronic postsurgical pain develops in 10% of patients undergoing surgery. Recently, multidisciplinary, patient-tailored interventions, such as a Transitional Pain Service (TPS) have been developed and implemented to improve perioperative pain management and thereby prevent chronic postsurgical pain. The purpose of this survey was to analyse health care providers satisfaction and learn from their experiences on the implementation of a TPS. In the TRUST study, a randomized controlled trial investigating the effectiveness of a TPS, 176 patients were enrolled. Afterwards, a satisfaction survey was internally developed, which consisted of eight items. Satisfaction was measured using a Likert scale with five response options from never (1 point) to always (5 points). Surveys were sent to all anaesthetists and anaesthesia residents in our department that were faced with the consequences of TPS implementation. In May 2022, 36 caregivers of the Department of Anaesthesiology returned the survey after four rounds of distribution, with a response rate of 82.3%. Thirty staff members (81.0%) strongly felt that patient care had improved with the introduction of a TPS and 33 (86.8%) would like to see the TPS to be continued in the future. Health care provider satisfaction improved after implementation of a TPS in our hospital.

Central neuropathic pain is not only characterized by reflexive pain responses, but also emotional or affective nonreflexive pain responses, especially in women. Some pieces of evidence suggest that the activation of the neuroimmune system may be contributing to the manifestation of mood disorders in patients with chronic pain conditions, but the mechanisms that contribute to the development and chronicity of CNP and its associated disorders remain poorly understood. This study aimed to determine whether neuroinflammatory factor over-expression in the spinal cord and supraspinal structures may be associated with reflexive and nonreflexive pain response development from acute SCI phase to 12 weeks post-injury in female mice. The results show that transient reflexive responses were observed during the SCI acute phase associated with transient cytokine overexpression in the spinal cord. In contrast, increased nonreflexive pain responses were observed in the chronic phase associated with cytokine overexpression in supraspinal structures, especially in mPFC. In addition, results revealed that besides cytokines, the mPFC showed an increased glial activation as well as CX3CL1/CX3CR1 upregulation in the neurons, suggesting the contribution of neuron-glia crosstalk in the development of nonreflexive pain responses in the chronic spinal cord injury phase.

In vivo corneal confocal microscopy (IVCM) allows the immediate analysis of the corneal nerve quantity and morphology. This method became, an indispensable tool for the tropism examination, as it evaluates the small fiber plexus in the cornea. The IVCM provides us with direct information on the health of the sub-basal nerve plexus and indirectly on the peripheral nerve status. It is an important tool used to investigate peripheral polyneuropathies. Small-fiber neuropathy (SFN) is a group of neurological disorders characterized by neuropathic pain symptoms and autonomic complaints due to the selective involvement of thinly myelinated Aδ-fibers and unmyelinated C-fibers. Accurate diagnosis of SFN is important as it provides a basis for etiological work-up and treatment decisions. The diagnosis of SFN is sometimes challenging as the clinical picture can be difficult to interpret and standard electromyography is normal. In cases of suspected SFN, measurement of intraepidermal nerve fiber density through a skin biopsy and/or analysis of quantitative sensory testing can enable diagnosis. The purpose of the present review is to summarize the current knowledge about corneal nerves in different SFN. Specifically, we explore the correlation between nerve density and morphology and type of SFN, disease duration, and follow-up. We will discuss the relationship between cataracts and refractive surgery and iatrogenic dry eye disease. Furthermore, these new paradigms in SFN present an opportunity for neurologists and clinical specialists in the diagnosis and monitoring the peripheral small fiber polyneuropathies.

Endometriosis (EM), defined as the presence of endometrial-like tissue with surrounding smooth muscle cells outside the uterus, is a disregarded gynecological disease reported to affect 6-10% of women of reproductive age, with 30-50% of them suffering from chronic pelvic pain and infertility. Since the exact pathogenic mechanisms of EM are still unclear, no curative therapy is available. As pain is an important factor in EM, optimal analgesia should be sought, which to date has been treated primarily with non-steroidal anti-inflammatory drugs (NSAIDs), metamizole or, in extreme cases, opioids. Here, we review the pain therapy options, the mechanisms of pain development in EM, the endogenous opioid system and pain, as well as the opioid receptors and EM-associated pain. We also explore the drug abuse and addiction to opioids and the possible use of NOP receptors in terms of analgesia and improved tolerability as a target for EM-associated pain treatment. Emerging evidence has shown a promising functional profile of bifunctional NOP/MOP partial agonists as safe and nonaddictive analgesics. However, until now, the role of NOP receptors in EM has not been investigated. This review offers a thought which still needs further investigation but may provide potential options for relieving EM-associated pain.

Free drug concentration in the blood sera is crucial for its appropriate activity. Serum albumin, the universal blood carrier protein, is responsible for transporting drugs and releasing them into the bloodstream. Therefore, a drug's binding to SA is especially important for its bioavailability and it is a key problem in the drug design process. In this paper, we present crystal structures of three animal serum albumin complexes: ovine, caprine, and leporine, with diclofenac, a popular non-steroidal anti-inflammatory drug that is used in therapy of chronic and acute pain. Details of diclofenac binding mode by the presented serum albumins are compared with analogous complexes of human and equine serum albumins. The analysis of the occupied binding pockets in crystal structures of the investigated serum albumins from different mammals shows that they have two common and a number of unique diclofenac binding sites. The most intriguing is the fact that the albumins from the described species are able to bind different numbers of molecules of this popular anti-inflammatory drug, but none of the binding sites overlap with ones in the human serum albumin.

This study aimed to examine the presence of neuropsychological deficits and their relationships with clinical, pharmacological, and neuropsychiatric characteristics in chronic migraine (CM) patients assessed during a headache-free period. We enrolled 39 CM patients (mean age: 45.4 years; male/female ratio: 3/36) and 20 age-, sex-, and education-matched healthy controls (HCs, mean age: 45.5 years; male/female ratio: 2/18) in a case-control study. All CM patients underwent a full and extensive clinical, neuropsychiatric, and neuropsychological evaluation to evaluate cognitive domains, including sustained attention (SA), information processing speed (IPS), visuospatial episodic memory, working memory (WM), and verbal fluency (VF), as well as depressive and anxiety symptoms. CM patients exhibited higher scores than HCs for all clinical and neuropsychiatric measures, but no differences were found in personality characteristics. Although more than half of the CM patients (54%) showed mild-to-severe neuropsychological impairment (NI), with the most frequent impairments occurring in short- and long-term verbal episodic memory and inhibitory control (in approximately 90% of these patients), almost half of the patients (46%) showed no NI. Moreover, the severity of NI was positively associated with the number of pharmacological treatments received. Remarkably, disease-related symptom severity and headache-related disability explained global neuropsychological performance in CM patients. The presence of cognitive and neuropsychiatric dysfunction during the interictal phase occurred in more than half of CM patients, increasing migraine-related disability and possibly exerting a negative impact on health-related quality of life and treatment adherence.

It has been proposed that mechanosensitive Piezo1 channels trigger migraine pain in trigeminal nociceptive neurons, but the mechanosensitivity of satellite glial cells (SGCs) supporting neuronal sensitization has not been tested before. Moreover, tools to monitor previous Piezo1 activation are not available. Therefore, by using live calcium imaging with Fluo-4 AM and labeling with FM1-43 dye, we explored a new strategy to identify Piezo channels' activity in mouse trigeminal neurons, SGCs, and isolated meninges. The specific Piezo1 agonist Yoda1 induced calcium transients in both neurons and SGCs, suggesting the functional expression of Piezo1 channels in both types of cells. In Piezo1-transfected HEK cells, FM1-43 produced only a transient fluorescent response, whereas co-application with Yoda1 provided higher transient signals and a remarkable long-lasting FM1-43 'tail response'. A similar Piezo1-related FM1-43 trapping was observed in neurons and SGCs. The non-specific Piezo channel blocker, Gadolinium, inhibited the transient peak, confirming the involvement of Piezo1 receptors. Finally, FM1-43 labeling demonstrated previous activity in meningeal tissues 3.5 h after Yoda1 washout. Our data indicated that trigeminal neurons and SGCs express functional Piezo channels, and their activation provides sustained labeling with FM1-43. This long-lasting labelling can be used to monitor the ongoing and previous activation of Piezo1 channels in the trigeminal nociceptive system, which is implicated in migraine pain.

The homotrimeric P2X7 receptor (P2X7R) is expressed by virtually all cells of the innate and adaptive immune system and plays a crucial role in various pathophysiological processes such as autoimmune and neurodegenerative diseases, inflammation, neuropathic pain and cancer. Consequently, the P2X7R is considered a promising target for therapy and diagnosis. As the development of tracers comes hand-in-hand with the development of potent and selective receptor ligands, there is a rising number of PET tracers available in preclinical and clinical studies. This review analyzes the development of P2X7R positron emission tomography (PET) tracers and their potential in various PET imaging applications.

The purpose of the present paper was to review the available evidence on intra-articular botulinum toxin (BTX) injection in the treatment of knee osteoarthritis and to compare it to other conservative treatment options. A systematic review of the literature was performed on the PubMed, Scopus, Cochrane Library, Web of Science, Pedro and Research Gate databases with the following inclusion criteria: (1) randomized controlled trials (RCTs), (2) written in the English language, and (3) published on indexed journals in the last 20 years (2001-2021) dealing with the use of BTX intra-articular injection for the treatment of knee OA. The risk of bias was assessed using the Cochrane Risk of Bias tool for RCTs. Nine studies involving 811 patients in total were included. Patients in the control groups received different treatments: conventional physiotherapy, hyaluronic acid injection or prolotherapy or a combination thereof in 5 studies, steroid infiltrative therapy (triamcinolone) in 1 study, placebo in 2, and local anesthetic treatment in 1 study. Looking at the quality of the available literature, two of the included studies reached "Good quality" standard, three were ranked as "Fair", and the rest were considered "Poor". No major complications or serious adverse events were reported following intra-articular BTX, which provided encouraging pain relief, improved motor function, and quality of life. Based on the available data, no clear indication emerged from the comparison of BTX with other established treatments for knee OA. The analysis of the available RCTs on BTX intra-articular injection for the treatment of knee OA revealed modest methodological quality. However, based on the data retrieved, botulinum toxin has been proven to provide good short-term outcomes, especially in patients with pain sensitization, by modulating neurotransmitter release, peripheral nociceptive transduction, and acting on the control of chronic pain from central sensitization.

Several papers have been published suggesting a probable role of inflammatory factors in the etiopathogenesis of migraine. In this study, we investigated the possible association between common variants in the genes (both genes, which are closely related, encode proteins involved in inflammatory and autoimmune responses) in the risk of migraine in a cohort of Caucasian Spanish participants. For this purpose, the frequencies of rs1922452, rs951818, and rs870849 genotypes and allelic variants, using a specific -based qPCR assay, were assessed in 290 patients diagnosed with migraine and in 300 healthy controls. The relationship of these variables with several clinical features of migraine was also analyzed. The frequencies of the analyzed genotypes did not differ significantly between the two study groups and were not related to the sex, age at onset of migraine, family history of migraine, presence or absence of aura, or the triggering effect of ethanol on migraine episodes. These results suggest a lack of association between common variants in the genes and the risk of developing migraine in the Caucasian Spanish population.

Atopic dermatitis (AD) is a common skin disease caused by genetic and environmental factors. However, the mechanisms underlying AD development remain unclear. In this study, we examined the genetic factors contributing to the onset of itch-associated scratching in different strains of mice. Interleukin-31 (IL-31) induces severe scratching and dermatitis in mice. However, the site of action of IL-31 remains unclear. Cutaneous IL-31 and IL-31 receptor A (IL-31RA) mRNAs in the dorsal root ganglion (DRG) are expressed exclusively in the AD model, i.e., NC/Nga mice. Here we evaluated the effects of repeated administration of IL-31 on the scratching behavior in NC/Nga, BALB/c, and C57BL/6 mice. The results showed that repeated administration of IL-31 significantly increased itch-associated scratching (LLS) behavior in the three strains of mice. One hour after an intravenous IL-31 injection, BALB/c mice showed alloknesis-like behavior. Mite infestation and IL-31 administration triggered itchy skin, increased LLS counts and DRG neuronal IL-31RA expression, and eventually caused dermatitis. The dermatitis severity and LLS counts induced by mite infestation and IL-31 administration were in the order NC/Nga &gt; BALB/c &gt; C57BL/6. In conclusion, neuronal IL-31RA expression in the DRG was the most important genetic factor affecting the severity of LLS and dermatitis in mice.

The trafficking of transient receptor potential (TRP) channels to the plasma membrane and the release of calcitonin gene-related peptide (CGRP) from trigeminal ganglion neurons (TGNs) are implicated in some aspects of chronic migraines. These exocytotic processes are inhibited by cleavage of SNAREs with botulinum neurotoxins (BoNTs); moreover, type A toxin (/A) clinically reduces the frequency and severity of migraine attacks but not in all patients for unknown reasons. Herein, neonatal rat TGNs were stimulated with allyl isothiocyanate (AITC), a TRPA1 agonist, and dose relationships were established to link the resultant exocytosis of CGRP with Ca influx. The CGRP release, quantified by ELISA, was best fit by a two-site model (EC of 6 and 93 µM) that correlates with elevations in intracellular Ca [Ca] revealed by time-lapse confocal microscopy of fluo-4-acetoxymethyl ester (Fluo-4 AM) loaded cells. These signals were all blocked by two TRPA1 antagonists, HC-030031 and A967079. At low [AITC], [Ca] was limited because of desensitisation to the agonist but rose for concentrations &gt; 0.1 mM due to a deduced non-desensitising second phase of Ca influx. A recombinant BoNT chimera (/DA), which cleaves VAMP1/2/3, inhibited AITC-elicited CGRP release to a greater extent than SNAP-25-cleaving BoNT/A. /DA also proved more efficacious against CGRP efflux evoked by a TRPV1 agonist, capsaicin. Nerve growth factor (NGF), a pain-inducing sensitiser of TGNs, enhanced the CGRP exocytosis induced by low [AITC] only. Both toxins blocked NGF-induced neuropeptide secretion and its enhancement of the response to AITC. In conclusion, NGF sensitisation of sensory neurons involves TRPA1, elevated Ca influx, and CGRP exocytosis, mediated by VAMP1/2/3 and SNAP-25 which can be attenuated by the BoNTs.

Chronic pain is reportedly associated with the transient receptor potential canonical 3 () gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the gene and chronic pain. The genomic samples from 194 patients underwent linkage disequilibrium (LD) analyses of 29 SNPs within and around the vicinity of the gene. We examined the associations between the SNPs and the susceptibility to chronic pain by comparing the genotype distribution of 194 patients with 282 control subjects. All SNP genotype data were extracted from our previous whole-genome genotyping results. Twenty-nine SNPs were extracted, and a total of four LD blocks with 15 tag SNPs were observed within and around the gene. We further analyzed the associations between these tag SNPs and chronic pain. The rs11726196 SNP genotype distribution of patients was significantly different from the control subjects even after multiple-testing correction with the number of SNPs. The TT + TG genotype of rs11726196 is often carried by chronic pain patients, suggesting a causal role for the T allele. These results contribute to our understanding of the genetic risk factors for chronic pain.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease involving the spine, peripheral joints, and entheses. This condition causes stiffness, pain, and significant limitation of movement. In recent years, several effective therapies have become available based on the use of biologics that selectively block cytokines involved in the pathogenesis of the disease, such as tumor necrosis factor-α (TNFα), interleukin (IL)-17, and IL-23. However, a significant number of patients show an inadequate response to treatment. Over 10 years ago, small synthetic molecules capable of blocking the activity of Janus kinases (JAK) were introduced in the therapy of rheumatoid arthritis. Subsequently, their indication extended to the treatment of other inflammatory rheumatic diseases. The purpose of this review is to discuss the efficacy and safety of these molecules in axSpA therapy.

Cocaine- and amphetamine-regulated transcript (CART) peptides are involved in several physiological and pathological processes, but their mechanism of action is unrevealed due to the lack of identified receptor(s). We provided evidence for the antihyperalgesic effect of CART(55-102) by inhibiting dipeptidyl-peptidase 4 (DPP4) in astrocytes and consequently reducing neuroinflammation in the rat spinal dorsal horn in a carrageenan-evoked inflammation model. Both naturally occurring CART(55-102) and CART(62-102) peptides are present in the spinal cord. CART(55-102) is not involved in acute nociception but regulates spinal pain transmission during peripheral inflammation. While the full-length peptide with a globular motif contributes to hyperalgesia, its N-terminal inhibits this process. Although the anti-hyperalgesic effects of CART(55-102), CART(55-76), and CART(62-76) are blocked by opioid receptor antagonists in our inflammatory models, but not in neuropathic Seltzer model, none of them bind to any opioid or G-protein coupled receptors. DPP4 interacts with Toll-like receptor 4 (TLR4) signalling in spinal astrocytes and enhances the TLR4-induced expression of interleukin-6 and tumour necrosis factor alpha contributing to inflammatory pain. Depending on the state of inflammation, CART(55-102) is processed in the spinal cord, resulting in the generation of biologically active isoleucine-proline-isoleucine (IPI) tripeptide, which inhibits DPP4, leading to significantly decreased glia-derived cytokine production and hyperalgesia.

Pain is an unpleasant subjective experience that is usually modified by complex multidimensional neuropsychological processes. Increasing numbers of neuroimaging studies in humans have characterized the hierarchical brain areas forming a pain matrix, which is involved in the different dimensions of pain components. Although mechanistic investigations have been performed extensively in rodents, the homologous brain regions involved in the multidimensional pain components have not been fully understood in the rodent brain. Herein, we successfully identified several brain regions activated in response to mechanical allodynia in neuropathic pain rat models using an alternative neuroimaging method based on 2-deoxy-2-[F]fluoro-d-glucose positron emission tomography (FDG PET) scanning. Regions such as the medial prefrontal cortex, primary somatosensory cortex hindlimb region, and the centrolateral thalamic nucleus were identified. Moreover, brain activity in these regions was positively correlated with mechanical allodynia-related behavioral changes. These results suggest that FDG PET imaging in neuropathic pain model rats enables the evaluation of regional brain activity encoding the multidimensional pain aspect. It could thus be a fascinating tool to bridge the gap between preclinical and clinical investigations.

Complex regional pain syndrome (CRPS) taxonomy has been updated with reported subtypes and is defined as primary pain alongside other chronic limb pain (CLP) conditions. We aimed at identifying CRPS clinical phenotypes that distinguish CRPS from other CLP conditions. Cluster analysis was carried out to classify 61 chronic CRPS and 31 CLP patients based on evoked pain (intensity of hyperalgesia and dynamic allodynia, allodynia area, and after-sensation) and psychological (depression, kinesiophobia, mental distress, and depersonalization) measures. Pro-inflammatory cytokine IL-6 and TNF-α serum levels were measured. Three cluster groups were created: 'CRPS' (78.7% CRPS; 6.5% CLP); 'CLP' (64.5% CLP; 4.9% CRPS), and 'Mixed' (16.4% CRPS; 29% CLP). The groups differed in all measures, predominantly in allodynia and hyperalgesia ( &lt; 0.001, η² &gt; 0.58). 'CRPS' demonstrated higher psychological and evoked pain measures vs. 'CLP'. 'Mixed' exhibited similarities to 'CRPS' in psychological profile and to 'CLP' in evoked pain measures. The serum level of TNF-αwas higher in the 'CRPS' vs. 'CLP' ( &lt; 0.001) groups. In conclusion, pain hypersensitivity reflecting nociplastic pain mechanisms and psychological state measures created different clinical phenotypes of CRPS and possible CRPS subtypes, which distinguishes them from other CLP conditions, with the pro-inflammatory TNF-α cytokine as an additional potential biomarker.

The study's objective was to develop a clinical prediction rule that predicts a clinically significant analgesic effect on chronic knee osteoarthritis pain after transcranial direct current stimulation treatment. This is a secondary analysis from a double-blind randomized controlled trial. Data from 51 individuals with chronic knee osteoarthritis pain and an impaired descending pain inhibitory system were used. The intervention comprised a 15-session protocol of anodal primary motor cortex transcranial direct current stimulation. Treatment success was defined by the Western Ontario and McMaster Universities' Osteoarthritis Index pain subscale. Accuracy statistics were calculated for each potential predictor and for the final model. The final logistic regression model was statistically significant ( &lt; 0.01) and comprised five physical and psychosocial predictor variables that together yielded a positive likelihood ratio of 14.40 (95% CI: 3.66-56.69) and an 85% (95%CI: 60-96%) post-test probability of success. This is the first clinical prediction rule proposed for transcranial direct current stimulation in patients with chronic pain. The model underscores the importance of both physical and psychosocial factors as predictors of the analgesic response to transcranial direct current stimulation treatment. Validation of the proposed clinical prediction rule should be performed in other datasets.

Neuropathic pain is a chronic pain caused by a disease or damage to the somatosensory nervous system. The knowledge about the complete mechanisms is incomplete, but the role of oxidative compounds has been evaluated. In this context, we highlight the transient potential receptor vanilloid 4 (TRPV4), a non-selective cation channel, that can be activated by oxidated compounds. In clinical trials, the TRPV4 antagonist (GSK2798745) has been well-tolerated in healthy volunteers. The TRPV4 activation by oxidative compounds, such as hydrogen peroxide (HO) and nitric oxide (NO), has been researched in neuropathic pain models. Thus, the modulation of TRPV4 activation by decreasing oxidated compounds could represent a new pharmacological approach for neuropathic pain treatment. Most models evaluated the TRPV4 using knockout mice, antagonist or antisense treatments and detected mechanical allodynia, hyposmotic solution-induced nociception and heat hyperalgesia, but this channel is not involved in cold allodynia. Only HO and NO were evaluated as TRPV4 agonists, so one possible target to reduce neuropathic pain should focus on reducing these compounds. Therefore, this review outlines how the TRPV4 channel represents an innovative target to tackle neuropathic pain signaling in models induced by trauma, surgery, chemotherapy, cancer, diabetes and alcohol intake.

Knee osteoarthritis (Knee OA) is an irreversible condition that causes bone deformity and degeneration of the articular cartilage that comprises the joints, resulting in chronic pain and movement disorders. The administration of cultured adipose-derived stem cells (ADSCs) into the knee joint cavity improves the clinical symptoms of Knee OA; however, the effect of synovial fluid (SF) filling the joint cavity on the injected ADSCs remains unclear. In this study, we investigated the effect of adding SF from Knee OA patients to cultured ADSCs prepared for therapeutic use in an environment that mimics the joint cavity. An increase in the viability of ADSCs was observed following the addition of SF. Gene expression profiling of SF-treated ADSCs using DNA microarrays revealed changes in several genes involved in cell survival. Of these genes, we focused on FOSL1, which is involved in the therapeutic effect of ADSCs and the survival and proliferation of cancer stem cells. We confirmed the upregulation of FOSL1 mRNA and protein expression using RT-PCR and western blot analysis, respectively. Next, we knocked down FOSL1 in ADSCs using siRNA and observed a decrease in cell viability, indicating the involvement of FOSL1 in the survival of ADSCs. Interestingly, in the knockdown cells, ADSC viability was also decreased by SF exposure. These results suggest that SF enhances cell viability by upregulating FOSL1 expression in ADSCs. For therapy using cultured ADSCs, the therapeutic effect of ADSCs may be further enhanced if an environment more conducive to the upregulation of FOSL1 expression in ADSCs can be established.

Capsaicin receptor, also known as transient receptor potential vanilloid 1 (TRPV1), is involved in pain physiology and neurogenic inflammation. Herein, we discovered the presence of TRPV1 in hepatic stellate cells (HSCs) and aimed to delineate its function in this cell type and liver fibrosis.

This cross-sectional study aims to find the prevalence of chronic pain and its correlation with the quality of life and vitamin D levels among hemodialysis patients in Palestine. We used the brief pain inventory, the medical outcomes study 36-item short-form health survey, and Serum 25-hydroxyvitamin D to assess chronic pain, quality of life, and vitamin D levels, respectively. The study included 200 patients, 38.1% (95% confidence interval 31.3-45.4%) of whom had chronic pain, and 77.7% (95% confidence interval 71.0-83.4%) had deficient Vitamin D levels. Quality of life scores were generally low, with the lowest in role emotional and physical functioning. Sex, comorbidities, and vitamin D level significantly correlate with pain severity. Employment, number of comorbidities, pain severity, and albumin level are significantly associated with the Physical component of quality of life. On the other hand, employment and pain severity are significantly related to the mental component of quality of life. In conclusion, low vitamin D levels, chronic pain, and low quality of life scores are common among hemodialysis patients. In addition, vitamin D is negatively correlated with pain severity. Therefore, healthcare workers should assess and manage hemodialysis patients' chronic pain to improve their quality of life and reduce suffering.

Dupilumab attenuates itch and skin inflammation in patients with atopic dermatitis (AD). However, itch-related events that are improved by dupilumab remain unclear. Therefore, the present study investigated changes in clinical scores, serum biomarkers, and the number of intraepidermal nerve fibers (IENFs) using skin biopsies and blood samples from 12 patients with moderate to severe AD before and after treatment with dupilumab. Clinical manifestations were assessed using eczema area and severity index (EASI) and visual analogue scale (VAS) scores at baseline and after 8 and 16 weeks of treatment. Serum levels of total immunoglobulin E (IgE), thymus and activation-regulated chemokine (TARC), interleukin (IL)-4, IL-13, IL-22, and IL-31 were examined by electrochemiluminescence, chemiluminescent enzyme immunoassays, ProQuantum immunoassays, and enzyme-linked immunosorbent assays (ELISA) at baseline and after 8 and 16 weeks of treatment. In skin biopsies from AD patients at baseline and after 16 weeks of treatment, IENFs were examined immunohistochemically with the anti-protein gene product (PGP) 9.5 antibody. The dupilumab treatment significantly improved EASI and VAS scores and decreased serum levels of TARC, IgE, and IL-22, whereas those of IL-13 and IL-31, and the number of IENFs remained unchanged and those of IL-4 increased. VAS scores were positively correlated with serum TARC, IL-22, and IgE levels and the degree of epidermal thickening. Serum IL-31 levels were positively correlated with the number of IENFs. These results suggest that serum TARC, IL-22, and IgE levels and epidermal thickness are itch-related events associated with dupilumab treatment and that serum IL-31 levels may reflect the degree of IENF density in AD patients. Therefore, dynamic changes may be used to assess the efficacy of dupilumab treatment to treat itching and inflammation in patients with AD.

Osteoarthritis (OA) is a multifactorial degenerative disease marked by the progressive deterioration of articular cartilage with inflammation of the synovium. OA's main symptoms include pain and function loss. Monosodium Iodoacetate (MIA) experimental model is widely-used for OS induction since it produces symptoms comparable to those occurring in humans.

Discontinuation of treatment with monoclonal antibodies (mAb) targeting the Calcitonin Gene-Related Peptide (CGRP) pathway leads to an increase in migraine frequency. We aimed to assess changes in free and total CGRP plasma concentrations after the discontinuation of CGRP(-receptor) mAbs. This prospective analysis included 59 patients with migraine ( = 25 erenumab, = 25 galcanezumab, = 9 fremanezumab) who discontinued mAbs after ≥8 months of treatment. Patients were visited at the time of the last mAb injection (V1) and 16 weeks later (V2). For control, 30 migraine patients without preventive drug therapy were included. We measured free CGRP plasma concentrations in the erenumab and fremanezumab group and total CGRP concentrations in the galcanezumab group. Free CGRP plasma concentrations did not change after treatment discontinuation [erenumab: V1 31.2 pg/mL (IQR 25.8-45.6), V2 30.3 pg/mL (IQR 22.9-47.6), = 0.65; fremanezumab V1 29.4 pg/mL (IQR 16.4-61.9), V2 34.4 (19.2-62.0), = 0.86]. Controls had similar CGRP values of 32.6 pg/mL (IQR 21.3-44.6). Total CGRP concentrations in the galcanezumab group were 5439.3 pg/mL (2412.7-6338.1) at V1, and decreased to 1853.2 pg/mL (1136.5-3297.0) at V2 ( &lt; 0.001). Cessation of treatment with CGRP(-R) mAbs did not have an impact on the free-circulating CGRP concentrations. Total CGRP decreased significantly after three months of treatment discontinuation.

Myopathies fall under the umbrella of rare diseases, however, muscle pain is a relevant, under-recognized symptom with limited treatment options. Carbamazepine is an oral sodium channel blocker approved for the treatment of seizures and neuropathic pain. In 54 individuals receiving carbamazepine for muscle pain, we retrospectively assessed the subjective treatment response, side effects, and reasons for carbamazepine discontinuation. The underlying diagnoses leading to muscle pain were diverse, ranging from metabolic ( = 5) and other hereditary ( = 9) to acquired ( = 2) myopathies and myotonia syndromes ( = 22). Under carbamazepine (daily dose 254 ± 138 mg), patients reported a significant reduction of pain, quantified by an 11-point numeric rating scale (-1.9 ± 1.8, &lt; 0.001). Compared to age- and sex-matched controls, our sensory assessment revealed a significant dysfunction of Aδ-nerve fibers in patients with chronic muscle pain. Neuropathic pain components identified by the painDETECT questionnaire or quantitative sensory testing did not seem to influence the reported treatment response. Side effects ( = 18) such as fatigue, elevated liver enzymes, and diarrhea, as well as lack of pain improvement ( = 6), led to carbamazepine discontinuation in 44.4% (24/54). Mediated by dysfunctional Aδ-nerve fibers, muscle pain is common in a variety of myopathies. Carbamazepine may reduce pain levels, but comes with therapy-limiting side effects.

Rheumatoid arthritis (RA) is a chronic, systemic immune disease that causes joint affection and even disability. Activated macrophages play an important role in the pathogenesis and progression of RA by producing pro-inflammatory factors. The use of dexamethasone (DXM) is effective in relieving the intractable pain and inflammatory progression of RA. However, long-term use of DXM is strongly associated with increased rates of diabetes, osteoporosis, bone fractures, and mortality, which hinders its clinical use. In this study, the dextran sulfate-cisaconitic anhydride-dexamethasone (DXM@DS-cad-DXM) micelles were prepared to treat RA by selectively recognizing scavenger receptor (SR) on the activated macrophages. The potent targeting property of DXM@DS-cad-DXM micelles to SR was by fluorescence microscope. Additionally, the effective accumulation and powerful anti-inflammatory activity of DXM@DS-cad-DXM micelles were observed in the inflamed joints of adjuvant-induced arthritis (AIA) rats after intravenous administration. Overall, DXM@DS-cad-DXM micelles are a potentially effective nanomedicine for targeted therapy of RA.

Osteoarthritis (OA), the most prevalent joint disease and the leading cause of disability, remains an incurable disease largely because the etiology and pathogenesis underlying this degenerative process are poorly understood. Low-grade inflammation within joints is a well-established factor that disturbs joint homeostasis and leads to an imbalance between anabolic and catabolic processes in articular cartilage; however, the complexity of the network between inflammatory factors that often involves positive and negative feedback loops makes current anti-cytokine therapy ineffective. MicroRNAs (miRNAs) have emerged as key regulators to control inflammation, and aberrant miRNAs expression has recently been linked to OA pathophysiology. In the present study, we characterized transcriptomic profiles of miRNAs in primary murine articular chondrocytes in response to a proinflammatory cytokine, IL-1β, and identified as the most responsive miRNA to IL-1β. was also found to be upregulated in human OA cartilage. We further demonstrated that knockdown of antagonized IL-1β-mediated inflammatory responses and IL-1β-induced catabolism in vitro, and silencing of in chondrocytes ameliorated articular cartilage destruction and reduced OA-evoked pain in an injury-induced murine OA model. Moreover, parallel RNA sequencing revealed that differentially expressed genes in response to IL-1β were enriched in pathways related to inflammatory processes, cartilage matrix homeostasis, and cell metabolism. Bioinformatic analyses of putative gene targets and following prediction of protein-protein interactions suggest a functional role of in mediating inflammatory processes and regulation of cartilage homeostasis. Our genetic and transcriptomic data define a crucial role of in OA pathogenesis and implicate modulation of in articular chondrocytes as a potential therapeutic strategy to alleviate OA.

Pregabalin is a drug used to treat neuropathic pain, and its use has increased substantially since 2007. Early trials found a strong treatment effect on pain for post-herpetic neuralgia and diabetic neuropathy. However more recent studies have failed to replicate these results.

Arthroplasty is an orthopedic surgical procedure that replaces a dysfunctional joint by an orthopedic prosthesis, thereby restoring joint function. Upon the use of the joint prosthesis, a wearing process begins, which releases components such as titanium dioxide (TiO) that trigger an immune response in the periprosthetic tissue, leading to arthritis, arthroplasty failure, and the need for revision. Flavonoids belong to a class of natural polyphenolic compounds that possess antioxidant and anti-inflammatory activities. Hesperidin methyl chalcone's (HMC) analgesic, anti-inflammatory, and antioxidant effects have been investigated in some models, but its activity against the arthritis caused by prosthesis-wearing molecules, such as TiO, has not been investigated. Mice were treated with HMC (100 mg/kg, intraperitoneally (i.p.)) 24 h after intra-articular injection of 3 mg/joint of TiO, which was used to induce chronic arthritis. HMC inhibited mechanical hyperalgesia, thermal hyperalgesia, joint edema, leukocyte recruitment, and oxidative stress in the knee joint (alterations in gp91, GSH, superoxide anion, and lipid peroxidation) and in recruited leukocytes (total reactive oxygen species and GSH); reduced patellar proteoglycan degradation; and decreased pro-inflammatory cytokine production. HMC also reduced the activation of nociceptor-sensory TRPV1 and TRPA1 neurons. These effects occurred without renal, hepatic, or gastric damage. Thus, HMC reduces arthritis triggered by TiO, a component released upon wearing of prosthesis.

Guidelines regarding long-term use with onabotulinumtoxinA (onaBT-A) in chronic migraine (CM) prophylaxis are lacking. This multicentric prospective real-life study aimed to assess the efficacy and safety of a long-term treatment. A total of 195 chronic migraine patients were treated with onaBT-A, every 3 months for 5 cycles (Phase 1). In the Phase 2 of the study, depending on response rate, patients were divided into "responders" (R), "partially responders" (PR) and "non-responders" (NR). Then, we proposed to R and PR patients to continue with an additional 12 months of treatment (additional 4 sessions). Response to treatment and adverse events were collected for the entire duration of the study. Of the 195 patients included (females 82.1%, mean age 47.4 ± 12.4), at the end of Phase 1 there were 52.3% of R patients, 17.9% of PR patients, 15.4% of NR patients and 14.4% drop-outs. During Phase 2 of treatment, R patients presented a maintenance of the improvement achieved during the first year of treatment, as well as PR patients. Except for three serious adverse events not related to treatment, all other adverse events were mild or moderate in severity and resolved without sequelae. In the literature, adherence to oral migraine-preventive medications among patients with CM was found to be less than 25%. The results of this prospective real-life multicenter study show efficacy, safety and adherence to a long-term treatment with onaBT-A.

Osteoarthritis (OA) is a common chronic skeletal disease in the elderly. There is no effective therapy to reverse disease severity and knee OA (KOA) progression, particularly at the late stage. This study aims to examine the effect of peripheral blood-derived mononuclear cells (PBMNCs) on pain and motor function rescue in patients with Kellgren-Lawrence (KL) grade II to IV KOA. Participants received one intra-articular (IA) injection of autologous PBMNCs. The mononuclear cells were isolated from peripheral blood, enriched by a specialized medium (MoFi medium), and separated by Ficoll-Paque solution. The isolated and enriched PBMNCs could differentiate into M1 and M2 macrophages . The anti-inflammatory effect of the PBMNCs was similar to that of bone marrow mesenchymal stem cells, evaluated by complete Freund's adjuvant-induced arthritis in rodents. A single-arm and open-label pilot study showed that patients' knee pain and motor dysfunction were significantly attenuated after the cell transplantation, assessed by visual analogue scale (VAS) and Knee injury and Osteoarthritis Outcome Score (KOOS) at 6 and 12 months post-treatment. Notably, the therapeutic effect of the PBMNCs treatment can be stably maintained for 24 months, as revealed by the KOOS scores. These preclinical and pilot clinical data suggest that IA injection of MoFi-PBMNCs might serve as a novel medical technology to control the pain and the progress of KOA.

This systematic review aimed to investigate the measurement properties of pain scoring instruments in farm animals. According to the PRISMA guidelines, a registered report protocol was previously published in this journal. Studies reporting the development and validation of acute and chronic pain scoring instruments based on behavioral and/or facial expressions of farm animals were searched. Data extraction and assessment were performed individually by two investigators using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) guidelines. Nine categories were assessed: two for scale development (general design requirements and development, and content validity and comprehensibility) and seven for measurement properties (internal consistency, reliability, measurement error, criterion and construct validity, responsiveness and cross-cultural validity). The overall strength of evidence (high, moderate, low, or very low) of each instrument was scored based on methodological quality, number of studies and studies' findings. Twenty instruments for three species (bovine, ovine and swine) were included. There was considerable variability concerning their development and measurement properties. Three behavior-based instruments scored high for strength of evidence: UCAPS (Unesp-Botucatu Unidimensional Composite Pain Scale for assessing postoperative pain in cattle), USAPS (Unesp-Botucatu Sheep Acute Composite Pain Scale) and UPAPS (Unesp-Botucatu Pig Composite Acute Pain Scale). Four instruments scored moderate for strength of evidence: MPSS (Multidimensional Pain Scoring System for bovine), SPFES (Sheep Pain Facial Expression Scale), LGS (Lamb Grimace Scale) and PGS-B (Piglet Grimace Scale-B). Most instruments (n = 13) scored low or very low for final overall evidence. Construct validity was the most reported measurement property followed by criterion validity and reliability. Instruments with reported validation are urgently required for pain assessment of buffalos, goats, camelids and avian species.

Dorsal root ganglia (DRG) plays an important role in mediating the peripheral sensation transduction through the primary afferent neurons in pain research. Neuropathic pain (NP) is a syndrome of hyperalgesia, spontaneous pain and allodynia caused by central or peripheral nerve injury. Recent trends of study are turning towards the development of therapies for the management of NP. Activation of autophagy in glial cells in the spinal cord has been reported to be associated with attenuation of NP, but the autophagic process in DRG is rarely studied.

Chronic pain affects a significant amount of the population and represents a heavy personal and socioeconomic burden. Chronic pain mechanisms can be categorized as nociceptive, neuropathic, or nociplastic. Although mechanism-based pain treatment is optimal, different types of pain mechanisms may overlap in patients. Recently, the biopsychosocial model with the multidisciplinary pain management program is widely accepted as one of the most effective methods to assess and manage chronic pain. The treatment of chronic pain consists of a personalized, stepwise, and multimodal approach that includes pharmacotherapy, psychotherapy, integrative treatments, and interventional procedures. Somatic and peripheral nerve blocks for the treatment of chronic pain are often deferred. With the increasing use of ultrasound in pain medicine, newly defined interfascial plane blocks, which may be performed alone or as an adjuvant to multimodal management, have gained popularity. Adequate pain management can improve physical functioning, mental health and quality of life indicators, and reduce pain chronification. The aim of this current article is to perform a comprehensive and updated review of existing treatment options, particularly interfascial plane blocks in chronic pain syndromes.

Tenoxicam (TX) is a non-steroidal anti-inflammatory agent that can be used to control pain in various ophthalmic lesions like cataracts, refractive surgery, and corneal abrasion. TX has a very slightly aqueous solubility of 0.072 mg/mL resulting in difficulty to be formulated in ophthalmic solutions. This study aims to improve TX solubility by converting it into its potassium salt to achieve a target of 10 mg/mL (1%w/v) concentration of TX in the desired aqueous medium for the formulation of aqueous ophthalmic solutions. The synthesized TX salt was characterized by different evaluation parameters such as solubility studies, H NMR, IR, and elemental analyses. Different TX potassium solutions were formulated at concentrations of 0.5% and 1% w/v using different viscosity-imparting agents. The prepared solutions were characterized for their physicochemical properties including visual inspection, pH, rheological, in vitro release, and kinetic behavior. Also, the formulations were biologically evaluated in vivo using male albino rabbits. The obtained results showed the successful synthesis of TX salt, as indicated by IR and NMR, and elemental analysis. The solubility study showed that the solubility of TX was improved hugely to 18 mg/mL (250-fold). In addition, the results showed that the prepared formulations showed acceptable physicochemical properties. The highest release rate was obtained with formula F1, which contains no viscosity-imparting agents. While as, the lowest release rate was obtained in the case of formula F9, composed of Pluronic F127 (12% w/v). The in vivo results showed that TX optimized ophthalmic solutions F8 and F9 inhibited the redness and edema in an extended or sustained manner.

Rapid growth in smartphone use has expanded opportunities to use mobile health (mHealth) technology to collect real-time patient-reported and objective biometric data. These data may have important implication for personalized treatments of degenerative spine disease. However, no large-scale study has examined the feasibility and acceptability of these methods in spine surgery patients.

The management of persistent postoperative pain still remains a clinical challenge currently. Although ropivacaine (RVC) is widely used for postoperative analgesia as a local anesthetic, the short half-life makes it difficult to achieve the desired duration of analgesia. Herein, a novel RVC sustained-release microspheres encapsulated by zeolite imidazole framework-8 (RVC@ZIF-8) was synthesized for the first time, which prolonged the sustained-release of RVC and decreased the resulting drug toxicity. RVC can continuously release in vitro for at least 96 h with high drug loading of 30.6% and RVC@ZIF-8 had excellent biocompatibility and low cytotoxicity. In sciatic nerve block model, the sensory block time of RVC@ZIF-8 was significantly prolonged compared with RVC, achieving more than 72 h post injection and no inflammation or lesion were found. Based on high drug loading, ideal sustained-release and superior biological safety, RVC@ZIF-8 will be a novel delivery material for local anesthetic with potential application.

The canonical Wnt pathway participates in inflammatory diseases and it is involved in neuropathic pain. This study evaluated the immunoexpression of the canonical Wnt signaling pathway in the articular cartilage of the temporomandibular joint (TMJ) and along the nociceptive trigeminal pathway in arthritic rats. For this, male Wistar rats were divided into Control (C) and Arthritic (RA) groups. Arthritis induction was performed through subcutaneous injection of methylated bovine serum albumin (mBSA) and complete Freund Adjuvant (CFA)/ Incomplete Freund Adjuvant (IFA) on the first 14 days (once a week), followed by 3 weekly intra-articular injections of mBSA (10 μl/joint; left TMJ). The following parameters were evaluated: nociceptive threshold, inflammatory infiltrate, type I and III collagen birefringence, immunohistochemistry for IL-1β, TNF-α, IL-6, Wnt10b, β-catenin, cyclin-D1 in articular cartilage, c-Myc in synovial membrane, and immunofluorescence analysis for c-Fos, Wnt-10b and β-catenin in the trigeminal ganglion and the trigeminal subnucleus caudalis. The RA group showed intense articular cartilage damage with proliferation of type III collagen, increased immunoexpression of proinflammatory cytokines and Wnt-10b, β-catenin and cyclin-D1 in the articular cartilage and c-Myc in the synovial membrane. In the RA group, a reduction in the nociceptive threshold was observed, followed by a significant increase in the expression of Wnt-10b in neurons and β-catenin in satellite cells of the trigeminal ganglion. c-Fos immunoexpression was observed in neurons, peripherally and centrally, in arthritic rats. Our data demonstrated that TMJ arthritis in rats causes articular cartilage damage and nociceptive behavior, with increased immunoexpression of canonical Wnt pathway in the articular cartilage and trigeminal ganglion.

Chemotherapy induced peripheral neuropathy (CIPN) is a particularly pernicious form of neuropathy and the associated pain is the primary dose-limiting factor of life-prolonging chemotherapy treatment. The prevalence of CIPN is high and can last long after treatment has been stopped. Currently, late in the COVID-19 pandemic, there are still increased psychological pressures on cancer patients as well as additional challenges in providing analgesia for them. These include the risks of nonsteroidal anti-inflammatory drug (NSAID) analgesics potentially masking early infection symptoms and the immunosuppression of steroidal and opiate based approaches. Even without these concerns, CIPN is often inadequately treated with few therapies that offer significant pain relief. The experiments we report use soluble epoxide hydrolase inhibitors (sEHI) which relieved this intractable pain in preclinical models. Doses of EC5026, an IND candidate intended to treat neuropathic pain, elicited dose dependent analgesic responses in multiple models including platinum-based, taxane, and vinca alkaloid-based CIPN pain in Sprague Dawley rats. At the same time as a class, the sEHI are known to result in fewer debilitating side effects of other analgesics, likely due to their novel mechanism of action. Overall, the observed dose-dependent analgesia in both male and female rats across multiple models of chemotherapy induced neuropathic pain holds promise as a useful tool when translated to the clinic.

Recent neuroimaging studies have indicated a wide range of structural and regional functional alterations in patients with classic trigeminal neuralgia (CTN). However, few studies have focused on the intrinsic functional characteristics of network organization in the whole brain. Therefore, the present study aimed to characterize the potential intrinsic dysconnectivity pattern of the whole brain functional networks at the voxel level using the degree centrality (DC) analysis in CTN patients.

Rheumatoid arthritis (RA) is a chronic destructive autoimmune disease of the joints which causes significant pain, functional disability, and mortality. Although aberrant immune cell activation induced by the imbalance between T helper Th1/Th17 and Treg cells is implicated in the RA development, its etiopathogenesis remains unclear. The presence of mucosal inflammation and systemic IgA-isotype-autoantibodies (anti-citrullinated peptide antibodies and rheumatoid factor) in pre-clinical RA supports the mucosal origin hypothesis involving altered microbiota in disease development. The gut microbiota comprises diverse bacteria, fungal and viral components, which are critical in developing host immunity. Alterations in microbial abundance are known to exacerbate or attenuate immune responses in the gut microenvironment subsequently affecting the joints. Further, these changes can provide biomarkers for disease activity and outcome in RA. Most of the research till date has been focused on describing gut bacterial components in RA. Studies on gut mycobiome and virome components in RA are relatively new and burgeoning field. Given the paucity of mycobiome or virome specific studies in RA, this review, discusses the recent findings on alterations in gut bacterial, fungal, and viral components as well as their role in regulating the spectrum of immune-pathogenic events occurring in RA which might be explored in future as a potential therapeutic target. Further, we provide an overview on inter-kingdom interactions between bacteria, fungi, and viruses in RA. The current understanding on gut microbiota modulation for managing RA is also summarised.

P2X3 receptors and group II metabotropic glutamate receptors (mGluRs) have been found to be expressed in primary sensory neurons. P2X3 receptors participate in a variety of pain processes, while the activation of mGluRs has an analgesic effect. However, it's still unclear whether there is a link between them in pain. Herein, we reported that the group II mGluR activation inhibited the electrophysiological activity of P2X3 receptors in rat dorsal root ganglia (DRG) neurons. Group II mGluR agonist LY354740 concentration-dependently decreased P2X3 receptor-mediated and α,β-methylene-ATP (α,β-meATP)-evoked inward currents in DRG neurons. LY354740 significantly suppressed the maximum response of P2X3 receptor to α,β-meATP, but did not change their affinity. Inhibition of ATP currents by LY354740 was blocked by the group II mGluR antagonist LY341495, also prevented by the intracellular dialysis of either the G protein inhibitor pertussis toxin, the cAMP analog 8-Br-cAMP, or the protein kinase A (PKA) inhibitor H-89. Moreover, LY354740 decreased α,β-meATP-induced membrane potential depolarization and action potential bursts in DRG neurons. Finally, intraplantar injection of LY354740 also relieved α,β-meATP-induced spontaneous nociceptive behaviors and mechanical allodynia in rats by activating peripheral group Ⅱ mGluRs. These results indicated that peripheral group II mGluR activation inhibited the functional activity of P2X3 receptors via a G protein and cAMP/PKA signaling pathway in rat DRG neurons, which revealed a novel mechanism underlying analgesic effects of peripheral group II mGluRs.

Clinical manifestations of classic Fabry disease (α-galactosidase A deficiency) usually occur in childhood, while complications involving major organs typically develop in adulthood. Outcomes of Fabry-specific treatment among young patients have not been extensively reported. Our aim was to analyze clinical outcomes among patients aged 5-30 years at initiation of treatment with agalsidase beta using data from the Fabry Registry (NCT00196742, sponsor: Sanofi).

Treatment of migraine in the setting of either renal or hepatic disease can be daunting for clinicians. Not only does the method of metabolism have to be considered, but also the method of elimination/excretion of the parent drug and any active or toxic metabolites. Furthermore, it is difficult to think about liver or kidney disease in isolation, as liver disease can sometimes contribute to impaired renal function and renal disease can sometimes impair hepatic metabolism, through the cytochrome P450 system.

Previous international mass-media campaigns for low back pain (LBP) have had conflicting impacts on the general population. The objective was to evaluate the impact of a national back pain campaign conducted between 2017 and 2019 on beliefs and behaviours of general practitioners and the general population in France.

Clinical treatment of acute to severe pain relies on the use of opioids. While their potency is significant, there are considerable side effects that can negatively affect patients. Their rise in usage has correlated with the current opioid epidemic in the United States, which has led to more than 70,000 deaths per year (Volkow and Blanco, 2021). Opioid-related drug development aims to make target compounds that show strong potency but with diminished side effects. Research into pharmaceuticals that could act as potential alternatives to current pains medications has relied on mechanistic insights of opioid receptors, a class of G-protein coupled receptors (GPCRs), and biased agonism, a common phenomenon among pharmaceutical compounds where downstream effects can be altered at the same receptor via different agonists. Opioids function typically by binding to an active site on the extracellular portion of opioid receptors. Once activated, the opioid receptor initiates a G-protein signaling pathway and/or the β-arrestin2 pathway. The proposed concept for the development of safe analgesics around mu and kappa opioid receptor subtypes has focused on not recruiting β-arrestin2 (biased agonism) and/or having low efficacy at the receptor (partial agonism). By altering chemical motifs on a common scaffold, chemists can take advantage of biased agonism as well as create compounds with low intrinsic efficacy for the desired treatments. This review will focus on ligands with bias profile, signaling aspects of the receptor and probe into the structural basis of receptor that leads to bias and/or partial agonism.

Seriously ill patients often experience persistent pain. As a part of a comprehensive repertoire of pain interventions, palliative care clinicians can help by using behavioral pain management. Behavioral pain management refers to evidence-based psychosocial interventions to reduce pain intensity and enhance functional outcomes and quality of life. Conceptualized using the biopsychosocial model, techniques involve promoting helpful behaviors (e.g., activity pacing, stretching, and relaxation exercises) and modifying underlying patterns of thinking, feeling, and communicating that can exacerbate pain. The authors have expertise in pain management, clinical health psychology, geropsychology, behavioral science, and palliative medicine. The article reviews the current evidence for behavioral interventions for persistent pain and provides 10 recommendations for behavioral pain management.

The fear-avoidance model of pain posits that a painful stimulus is interpreted through pain catastrophizing, which leads to negative downstream cognitions, emotions, and behaviors that shape the experience of pain. As dispositional mindfulness is associated with less catastrophizing and pain, some researchers have suggested incorporating mindfulness into the fear-avoidance model. Across two studies, we empirically tested dispositional mindfulness as a stand-alone component within the fear-avoidance model of pain.

Subcutaneous infiltration of capsaicin, which initially activates transient receptor potential vanilloid 1 (TRPV1) receptors, can subsequently desensitize TRPV1-expressing nociceptors and induce analgesia in different pain models. Yet, whether the modulation of keratinocytes may also contribute to the analgesic action of capsaicin treatment remains unclear. In a rat model of postoperative pain, we tested the hypothesis that subcutaneous injection of capsaicin inhibited the proliferation of epidermal keratinocytes and their expression of pronociceptive inflammatory mediators after plantar incision.