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Opioids, such as morphine and fentanyl, are widely used for the treatment of severe pain; however, prolonged treatment with these drugs leads to the development of tolerance and can lead to opioid use disorder. The "Opioid Epidemic" has generated a drive for a deeper understanding of the fundamental signaling mechanisms of opioid receptors. It is generally thought that the three types of opioid receptors (μ, δ, κ) are activated by endogenous peptides derived from three different precursors: Proopiomelanocortin, proenkephalin, and prodynorphin. Posttranslational processing of these precursors generates >20 peptides with opioid receptor activity, leading to a long-standing question of the significance of this repertoire of peptides. Here, we address some aspects of this question using a technical tour de force approach to systematically evaluate ligand binding and signaling properties ([S]GTPγS binding and β-arrestin recruitment) of 22 peptides at each of the three opioid receptors. We show that nearly all tested peptides are able to activate the three opioid receptors, and many of them exhibit agonist-directed receptor signaling (functional selectivity). Our data also challenge the dogma that shorter forms of β-endorphin do not exhibit receptor activity; we show that they exhibit robust signaling in cultured cells and in an acute brain slice preparation. Collectively, this information lays the groundwork for improved understanding of the endogenous opioid system that will help in developing more effective treatments for pain and addiction.
Learn More >The sodium channels Na1.7, Na1.8 and Na1.9 are critical for pain perception in peripheral nociceptors. Loss of function of Na1.7 leads to congenital insensitivity to pain in humans. Here we show that the spider peptide toxin called HpTx1, first identified as an inhibitor of K4.2, restores nociception in Na1.7 knockout (Na1.7-KO) mice by enhancing the excitability of dorsal root ganglion neurons. HpTx1 inhibits Na1.7 and activates Na1.9 but does not affect Na1.8. This toxin produces pain in wild-type (WT) and Na1.7-KO mice, and attenuates nociception in Na1.9-KO mice, but has no effect in Na1.8-KO mice. These data indicate that HpTx1-induced hypersensitivity is mediated by Na1.9 activation and offers pharmacological insight into the relationship of the three Na channels in pain signalling.
Learn More >HDAC6 is a class IIB histone deacetylase expressed at many levels of the nociceptive pathway. This study tested the ability of novel and selective HDAC6 inhibitors to alleviate sensory hypersensitivity behaviors in mouse models of peripheral nerve injury and peripheral inflammation.
Learn More >Neuroinflammation is implicated in the development and maintenance of persistent pain states, but there is limited data linking cerebrospinal fluid (CSF) inflammatory mediators with neurophysiological pain processes in humans.In a prospective observational study, CSF inflammatory mediators were compared between patients with osteoarthritis (OA) who were undergoing total hip arthroplasty due to disabling pain symptoms (n=52) and pain-free comparison controls (n=30). In OA patients only, detailed clinical examination and quantitative sensory testing were completed. CSF samples were analyzed for ten proinflammatory mediators using Meso Scale Discovery platform.Compared to controls, OA patients had higher CSF levels of interleukin 8 (IL-8) (P=0.002), intercellular adhesion molecule (ICAM) 1 (P=0.007) and vascular cell adhesion molecule (VCAM) 1 (P=0.006). OA patients with central sensitization possibly indicated by arm pressure pain detection threshold (PPDT) <250 kPa showed significantly higher CSF levels of Fms related tyrosine kinase 1 (Flt-1) (P=0.044) and interferon gamma-induced protein 10 (IP-10) (P=0.024), as compared to subjects with PPDT above that threshold. In patients reporting pain numerical rating scale score ≥3/10 during peripheral venous cannulation (PVC), Flt-1 was elevated (P=0.025), and in patients with punctate stimulus wind-up-ratio ≥2, CSF monocyte chemoattractant protein 1 (MCP-1) was higher (P=0.011). Multiple logistic regression models showed that increased Flt-1 was associated with central sensitization, assessed by remote site PPDT and PVC pain, and MCP-1 with temporal summation in the area of maximum pain.Multiple proinflammatory mediators measured in CSF are associated with persistent hip OA-related pain. Pain phenotype may be influenced by specific CSF neuroinflammatory profiles.
Learn More >Ketamine and Magnesium for Refractory Neuropathic Pain: A Randomized, Double-blind, Crossover Trial.
Ketamine is often used for the management of refractory chronic pain. There is, however, a paucity of trials exploring its analgesic effect several weeks after intravenous administration or in association with magnesium. The authors hypothesized that ketamine in neuropathic pain may provide pain relief and cognitive-emotional benefit versus placebo and that a combination with magnesium may have an additive effect for 5 weeks.
Learn More >Attending towards pain is proposed as a key mechanism influencing the experience and chronification of pain. Persistent attention toward pain is proposed to drive poor outcomes in both adults and children with chronic pain. However, there are no validated self-report measures of pain-related attention for children.
Learn More >The mu opioid receptor (MOR) modulates nociceptive pathways, reward processing, and mediates the strong analgesic and addictive properties of both medicinal as well as abused opioid drugs. MOR function has been extensively studied, and tools to manipulate or visualize the receptor protein are available. However, circuit mechanisms underlying MOR-mediated effects are less known, because genetic access to MOR-expressing neurons is lacking. Here we report the generation of a knock-in -Cre mouse line, which allows targeting and manipulating MOR opioid-responsive neurons. A cDNA encoding a T2A cleavable peptide and Cre-recombinase fused to enhanced green fluorescent protein (eGFP/Cre) was inserted downstream of the gene sequence. The resulting Cre line shows intact gene transcription. MOR and eGFP/Cre proteins are co-expressed in the same neurons, and localized in cytoplasmic and nuclear compartments, respectively. MOR signaling is unaltered, demonstrated by maintained DAMGO-induced G protein activation, MOR function is preserved as indicated by normal morphine-induced analgesia, hyperlocomotion and sensitization. The Cre-recombinase efficiently drives expression of Cre-dependent reporter genes, shown by local-virally-mediated expression in the medial habenula and brain wide fluorescence upon breeding with tdTomato reporter mice, the later showing a distribution patterns typical of MOR expression. Finally, we demonstrate that optogenetic activation of MOR neurons in the ventral tegmental area of -Cre mice evokes strong avoidance behavior, as anticipated from the literature. The -Cre line is therefore an excellent tool for both mapping and functional studies of MOR-positive neurons, and will be of broad interest for opioid, pain and addiction research. Here we develop an innovative tool to characterize circuit mechanisms underlying opioid actions, which may help the research communities to improve the knowledge on circuitry adaptation and response to opioid. The tool is particularly relevant in the context of the current opioid crisis. Medicinal and abused opioids act primarily on Mu Opioid Receptor (MOR) and we developed here a Cre mouse line to specifically target and manipulate MOR-expressing neurons. This resource is with huge potential for mapping, molecular characterization and functional studies of opioid-responsive neurons.
Learn More >Morphine and other opioids are commonly used to treat pain despite their numerous adverse side effects. Modulating μ-opioid receptor (MOR) signaling is one way to potentially improve opioid therapy. In mice, the chaperone protein Hsp90 mediates MOR signaling within the brain. Here, we found that inhibiting Hsp90 specifically in the spinal cord enhanced the antinociceptive effects of morphine in mice. Intrathecal, but not systemic, administration of the Hsp90 inhibitors 17-AAG or KU-32 amplified the effects of morphine in suppressing sensitivity to both thermal and mechanical stimuli in mice. Hsp90 inhibition enabled opioid-induced phosphorylation of the kinase ERK and increased abundance of the kinase RSK in the dorsal horns of the spinal cord, which are heavily populated with primary afferent sensory neurons. The additive effects of Hsp90 inhibition were abolished upon intrathecal inhibition of ERK, RSK, or protein synthesis. This mechanism downstream of MOR, localized to the spinal cord and repressed by Hsp90, may potentially be used to enhance the efficacy and presumably decrease the side effects of opioid therapy.
Learn More >ANO1 (TMEM16A) is a Ca-activated Cl channel (CaCC) expressed in peripheral somatosensory neurons that are activated by painful (noxious) stimuli. These neurons also express the Ca-permeable channel and noxious heat sensor TRPV1, which can activate ANO1. Here, we revealed an intricate mechanism of TRPV1-ANO1 channel coupling in rat dorsal root ganglion (DRG) neurons. Simultaneous optical monitoring of CaCC activity and Ca dynamics revealed that the TRPV1 ligand capsaicin activated CaCCs. However, depletion of endoplasmic reticulum (ER) Ca stores reduced capsaicin-induced Ca increases and CaCC activation, suggesting that ER Ca release contributed to TRPV1-induced CaCC activation. ER store depletion by plasma membrane-localized TRPV1 channels was demonstrated with an ER-localized Ca sensor in neurons exposed to a cell-impermeable TRPV1 ligand. Proximity ligation assays established that ANO1, TRPV1, and the IP receptor IPR1 were often found in close proximity to each other. Stochastic optical reconstruction microscopy (STORM) confirmed the close association between all three channels in DRG neurons. Together, our data reveal the existence of ANO1-containing multichannel nanodomains in DRG neurons and suggest that coupling between TRPV1 and ANO1 requires ER Ca release, which may be necessary to enhance ANO1 activation.
Learn More >Patients undergoing cancer treatment often experience chemotherapy-induced neuropathic pain at their extremities, for which there is no U.S. Food and Drug Administration-approved drug. The authors hypothesized that local sympathetic blockade, which is used in the clinic to treat various pain conditions, can also be effective to treat chemotherapy-induced neuropathic pain.
Learn More >Trigeminal neuropathic pain (TNP) is often resistant to current pharmacotherapy and there is a pressing need to develop more efficacious treatments. Capsaicin is a pungent ingredient of chili peppers and specifically activates transient receptor potential vanilloid subtype 1 (TRPV1), a Ca-permeable ion channel. Topical capsaicin invariably induces burning pain. Paradoxically, the transient pain is often followed by prolonged attenuation of the pre-existing pathological pain from the same region. However, the mechanisms underlying capsaicin-induced analgesia are not well understood. Although the reports of the involvement of TRPV1 and TRPV1+ afferents in neuropathic pain is controversial, we recently demonstrated that TRPV1 and TRPV1+ afferents are involved in mechanical hyperalgesia in mice with chronic constriction injury of the infraorbital nerve (ION-CCI). Consistently, chemogenetic inhibition of TRPV1-lineage afferents attenuated mechanical hyperalgesia and ongoing pain. In mice with ION-CCI, we found that a single focal injection of capsaicin into facial skin led to attenuation of mechanical hyperalgesia over two weeks. Capsaicin treatment also attenuated secondary hyperalgesia in extraterritorial mandibular skin. Furthermore, capsaicin treatment decreased ongoing pain. Longitudinal two-photon imaging of cutaneous nerve fibers showed that such capsaicin-induced analgesia is correlated with cutaneous nerve terminal density. Furthermore, preventing capsaicin-induced ablation of afferent terminals by co-administration of capsaicin with MDL28170, an inhibitor of calpain, abolished capsaicin-induced analgesia. These results suggest that a single focal injection of capsaicin induces long-lasting analgesia for neuropathic pain via selective ablation of TRPV1+ afferent terminals and that TRPV1+ afferents contribute to the maintenance of trigeminal neuropathic pain. Capsaicin has long been used as an analgesic to treat chronic pain conditions. Topical capsaicin is a FDA-approved treatment for neuropathic pain. However, the mechanisms underlying capsaicin-induced analgesia have been enigmatic for centuries. Despite evidence for clinical analgesia, data supporting the analgesic effects of capsaicin on neuropathic pain in preclinical model is rare. We found that a single focal injection of capsaicin to facial skin robustly attenuated trigeminal neuropathic pain in mice for longer than two weeks, which is mediated by localized ablation of TRPV1+ terminals in the skin. These results suggest that TRPV1+ afferents contribute to the maintenance of TNP and that capsaicin injection could be a safe and effective treatment for TNP.
Learn More >Cumulative evidence supports the association between perceived childhood neglect and adulthood psychological and physical health. To date, pathways mediating this association remain largely unknown, though other evidence suggests that negative patterns of appraisal, including injustice perception related to pain, may be shaped by prior adverse social experiences. Consequently, the current study examined perceived injustice about chronic pain as a possible factor connecting childhood neglect and pain-related outcomes, given its relevance for both adaptation to chronic pain and to prior adverse life experiences. Patients (n = 742) visiting a tertiary pain clinic completed a survey administered via the Collaborative Health Outcomes Information Registry. Path modeling analyses were used to examine perceived injustice as a mediator of the relationships between childhood neglect and affective distress and physical function, after controlling for pain intensity and pain catastrophizing. Patients endorsing childhood neglect reported higher levels of perceived injustice and worse affective distress and physical function. Further, inclusion of perceived injustice as a mediator fully accounted for the relationship between neglect and current levels of physical function, and accounted for a significant proportion of the relationship between neglect and current levels of affective distress. These preliminary findings suggest that perceived injustice appears to be a more proximal factor by which prior experiences of neglect may adversely affect adaptation to chronic pain. Given the single-item assessment of childhood neglect and cross-sectional nature of the current findings, further research may focus on replicating these findings in longitudinal studies with validated measures and examining other adverse social experiences (e.g., abuse, social disparities) that may contribute to injustice perception and poor pain-related outcomes.
Learn More >Synaptic neurotransmission with dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is terminated primarily by reuptake into presynaptic terminals via the DA, NE, and 5-HT transporters (DAT/NET/SERT, respectively). Monoamine transporter inhibitors constitute one class of drugs used to treat both depression and pain, and therapeutic effects by these compounds often require repeated treatment for days or weeks.
Learn More >There is an unmet medical need for pruritus associated with chronic kidney disease, a distressing complication characterized by generalized and persistent itch affecting 20% to 40% of patients undergoing hemodialysis. Here we report the results of a phase 2 trial evaluating the efficacy and safety of a novel peripherally restricted kappa opioid receptor agonist, difelikefalin, in adult patients undergoing hemodialysis with pruritus.
Learn More >Chronic pain affects 50% of adults with sickle cell disease (SCD). Although inflammation is thought to contribute to the pathogenesis of chronic pain, no studies have examined the differences in circulating cytokines between patients with SCD with and without chronic pain. We performed an observational cohort study using blood and urine samples from adults with SCD with and without chronic pain at their usual state of health. We tested the hypothesis that, compared to those without chronic pain, those with chronic pain would have significantly higher baseline circulating proinflammatory cytokines. A total of 61 adults with SCD, 40 with chronic pain and 21 without chronic pain were tested. When SCD patients with chronic pain were compared to those without chronic pain, no significant differences in cytokine levels were noted. The variables most associated with the diagnosis of chronic pain in this population were opioid dose and subject age.
Learn More >Chronological age is a risk factor in chronic pain; however, aging research supports the premise that physical and psychological health may better predict perceived age. Given the lack of evidence on perceived age in the context of chronic pain, the current study presents novel findings about the relationship between perceived age, chronic pain impact, and psychological function in adults with and without knee osteoarthritis.
Learn More >Headache disorders like migraine show geographic and ethnic differences between Asian and European/North American countries. In cluster headache, these differences are rarely mentioned and discussed. This article aimed to review the characteristics of cluster headache in Asian countries and compare the clinical features to those in European and North American populations.
Learn More >Background Migraine is a common disorder with high social and medical impact. Patients with migraine have a much higher chance of experiencing headache attacks as compared to the general population. Recent neuroimaging studies have confirmed that pathophysiology in the brain is not limited to the moment of the attack but is also present in between attacks, the interictal phase. Methods In this study, we hypothesized that the topology of functional brain networks is also different in the interictal state, compared to people who are not affected by migraine. We also expected that the level of network disturbances scales with the number of years people have suffered from migraine. Functional connectivity between 78 cortical brain regions was estimated for source-level magnetoencephalography (MEG) data by calculating the Phase Lag Index (PLI), in five frequency bands (delta-beta), and compared between healthy controls (n=24), and patients who had been suffering from migraine longer than 6 years (n=12) or shorter than 6 years (n=12). Moreover, the topology of the functional networks was characterized using the Minimum Spanning Tree (MST). Results The migraine groups did not differ from each other in functional connectivity. However, the network topology was different as compared to healthy controls. The results were frequency specific, and higher average nodal betweenness centrality was specifically evident in higher frequency bands in patients with a longer disease duration, while an opposite trend was present for lower frequencies. Conclusion This study shows that patients with migraine have a different network topology in the resting-state as compared to healthy controls, whereby specific brain areas have altered topological roles in a frequency specific manner. Some alterations appear specifically in patients with long-term migraine, which might show the long-term effects of the disease.
Learn More >Although opioids can be effective medications in certain situations, they are associated with harms, including opioid use disorder and overdose. Studies have revealed unexplained prescribing variation and prescribing mismatched with patient-reported pain for many indications.
Learn More >Recently the voltage-gated sodium (Nav) channels began to be studied as possible targets for analgesic drugs. In addition, specific Nav 1.8 blockers are currently being used to treat some types of chronic pain pathologies such as neuropathies and fibromyalgia. Nav 1.8 fibers convey nociceptive information to brain structures belonging to the limbic system, which is involved in the pathophysiology of major depressive disorders. From this, using a model of chronic social defeat stress (SDS) and intrathecal injections of Nav 1.8 antisense, this study investigated the possible involvement of Nav 1.8 nociceptive fibers in SDS- induced hyperalgesia in C57/BL mice. Our results showed that SDS induced a depressive-like behavior of social avoidance and increased the sensitivity to mechanical (electronic von Frey test) and chemical (capsaicin test) nociceptive stimuli. We also showed that intrathecal injection of Nav 1.8 antisense reversed the SDS-induced hyperalgesia as demonstrated by both, mechanical and chemical nociceptive tests. We confirmed the antisense efficacy and specificity in a separate no-defeated cohort through real-time PCR, which showed a significant reduction of Nav 1.8 mRNA and no reduction of Nav 1.7 and Nav 1.9 in the L4, L5 and L6 dorsal root ganglia (DRG). The present study advances the understanding of SDS-induced hyperalgesia, which seems to be dependent on Nav 1.8 nociceptive fibers.
Learn More >Recent evidence suggests that insomnia negatively influences the occurrence of generalized pain. This study examined whether insomnia is a risk factor for the transition from local pain to generalized pain (i.e., spreading of pain).
Learn More >When treating migraine patients in the current era of Coronavirus Disease 2019 (COVID-19), many institutions have moved away from face-to-face procedures like onabotulinumtoxinA injections, sometimes transitioning to the newer CGRP antibodies for migraine prevention. However, despite our best efforts to mitigate viral transmission, many of our migraine patients may eventually be exposed to SARS-CoV2. While most patients will have mild to moderate symptoms, a subset will become severely ill, with possible complications including respiratory failure and acute respiratory distress syndrome (ARDS). Given the possibility of this level of severe respiratory illness, we should consider what effect blocking calcitonin gene-related peptide (CGRP) might have on these patients.
Learn More >Background and aims Psychological traits such as pain catastrophizing may play a role in the development of chronic pelvic pain (CPP). Pain catastrophizing is the tendency to amplify negative cognitive and emotional pain processes. The Pain Catastrophizing Scale (PCS) assesses elements of pain catastrophizing divided into three subgroups of factors (rumination, helplessness and magnification). Previous studies have shown associations between CPP and increased pain sensitivity, widespread generalized hyperalgesia, and decreased pain thresholds, but the relation between pain catastrophizing and specific pain thresholds has not yet been widely examined in this patient group. The aims of this study were (a) to determine if catastrophizing is increased in women with CPP compared with pain-free women, (b) to assess the importance of pain catastrophizing, psychological distress variables, and subjective pain sensitivity for pain thresholds of heat, cold and pressure in these two groups, and (c) to determine whether psychological variables or pain thresholds best contribute to the differentiation between CPP and controls. Methods Thirty-seven women with chronic pelvic pain who underwent diagnostic laparoscopy on the suspicion of endometriosis participated along with 55 healthy and pain-free controls. All underwent quantitative sensory testing on six locations on the body to determine heat (HPT), cold (CPT) and pressure (PPT) pain thresholds. The PCS, the Pain Sensitivity Questionnaire (PSQ), the Hospital Anxiety Depression Scale, (HADS) demographics and clinical data were collected prospectively. Principal component analysis and orthogonal partial least square regressions were used to assess the associations between PCS scores and pain thresholds. Results The women with CPP scored significantly higher on PCS than the healthy controls. PCS-helplessness, PCS-rumination and HADS-depression were significantly associated with pain thresholds for the whole group. In the CPP group, PCS-rumination, body mass index and PSQ were significant regressors for HPT and CPT. The PCS and the HADS subscales were strongly intercorrelated in women with CPP and were stronger regressors of group membership than the three pain thresholds. In the group of healthy control women, no relationships were found to be significant. The psychological variables were somewhat stronger significant regressors than pain thresholds (also significant) for group membership. Conclusions Women with CPP have significantly higher pain catastrophizing scores than women without CPP. The pain catastrophizing rumination factor is significantly associated with pain thresholds of heat and cold in CPP women. PCS and HADS are strongly intercorrelated and PSQ correlates positively with these variables. It seems that the psychological variables are important for group differentiation. Implications The results clearly indicate the need for a multimodal assessment (bio-psycho-social) of CPP patients including psychological symptoms such as catastrophizing, anxiety and depression. The registration of semi-objective pain thresholds captures both specific pain sensitivity information (mechanical pressure, cold or heat) and the degree of wide spread pain hypersensitivity. There is a need for future larger studies investigating whether certain profiles in the clinical presentations (including pain thresholds and psychological variables) are associated with outcomes after different types of interventions.
Learn More >Recent evidence from event-related potentials (ERPs) has identified N2 posterior contralateral (pc) amplitudes as a neural marker of early attention allocation. The N2pc has been used to evaluate attention biases (ABs) in samples with anxiety-based problems but its utility has yet to be considered among persons with chronic pain, another group theorized to display ABs that perpetuate their difficulties. To address this gap, we assessed N2pc responses of adults with chronic pain (N = 70) and pain-free controls (N = 70) during a dot-probe task comprising painful-neutral and happy-neutral facial expression image pairs. Analyses indicated that (1) larger N2pc amplitudes were elicited by both painful and happy expressions compared to complementary neutral expressions in each sample, (2) the chronic pain sample displayed larger N2pc amplitudes during exposure to both painful and happy expressions than controls did, and (3) no group differences were evident for N2pc latencies. Overall N2pc results reflected general biases in early allocation of attention toward affectively-valenced expressions rather than pain-specific ABs among chronic pain cohorts.
Learn More >Many questions regarding the process by which self-enhancing humor style has an effect on chronic pain individuals' adjustment remain unanswered. The aim of the present study was to analyse the association of self-enhancing humor style with adjustment in a sample of individuals with chronic pain, over and above the role of catastrophizing and pain intensity. Adjustment was assessed using measures of depression, pain interference, and flourishing. We also examined the indirect association between self-enhancing humor style and adjustment via pain acceptance.
Learn More >To determine the perceived benefits of in older adults with chronic low-back pain (cLBP). A qualitative analysis from a randomized controlled feasibility trial. Eighteen participants (65+ years old) with cLBP of at least moderate intensity. A 36-week intervention beginning with twice weekly classes for 12 weeks, weekly classes for 6 weeks, biweekly classes for 6 weeks, and monthly classes for 12 weeks. Participants were asked to practice at home on nonclass days and videos were provided to assist in that process. Participants in the focus groups were asked to provide feedback on their experiences with the study as well as the benefits of their practice. We used demographic and class attendance data to describe the sample. Regarding the benefits of practice, five major themes were identified: functional benefits, pain reduction/pain relief, psychospiritual benefits, the importance of social support in learning , and the integration of into daily activities. The most common functional benefits were improvements in balance, flexibility, leg strength, and posture. Some reported pain reduction or pain relief, but others did not. Increased relaxation, mindfulness, and a sense of connectedness were subthemes that emerged from psychospiritual benefits. Social support benefits included motivation to attend class and group support while learning a new skill. Finally, improved body awareness allowed participants to integrate skills into their daily activities. This qualitative analysis demonstrates the multifaceted benefits of for older adults living with cLBP.
Learn More >Psychological stress is a trigger for the development of irritable bowel syndrome (IBS) and associated symptoms including abdominal pain. Although IBS patients exhibit increased activation in the limbic brain, including the amygdala, the underlying molecular and cellular mechanisms regulating visceral nociception in the central nervous system (CNS) are incompletely understood. In a rodent model of chronic stress, we explored the role of microglia in the central nucleus of amygdala (CeA) in controlling visceral sensitivity. Microglia are activated by environmental challenges such as stress, and are able to modify neuronal activity via synaptic remodeling and inflammatory cytokine release. Inflammatory gene expression and microglial activity are negatively regulated by nuclear glucocorticoid receptors (GR), which are suppressed by the stress-activated pain mediator P38 MAPK.
Learn More >Alterations in the brain's μ-opioid receptor (MOR) system have been associated with several neuropsychiatric diseases. Also healthy individuals vary considerably in MOR availability. Multiple epidemiological factors have been proposed to influence MOR system, but due to small sample sizes the magnitude of their influence remains inconclusive. We compiled [C]carfentanil positron emission tomography scans from 204 individuals with no neurologic or psychiatric disorders, and estimated the effects of sex, age, body mass index (BMI) and smoking on [C]carfentanil binding potential using between-subject regression analysis. We also examined hemispheric differences in MOR availability. Older age was associated with increase in MOR availability in frontotemporal areas but decrease in amygdala, thalamus, and nucleus accumbens. The age-dependent increase was stronger in males. MOR availability was globally lowered in smokers but independent of BMI. Finally, MOR availability was higher in the right versus the left hemisphere. The presently observed variation in MOR availability may explain why some individuals are prone to develop MOR-linked pathological states, such as chronic pain or psychiatric disorders. Lateralized MOR system may reflect hemispheric work distribution in central emotion and pain processes.
Learn More >To assess the long-term analgesic effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex in patients with chronic pain syndrome.
Learn More >Brain-derived neurotrophic factor (BDNF), a major focus for regenerative therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, studies of tyrosine receptor kinase B (TrkB), a major receptor for BDNF, indicate that certain effects of the TrkB receptor in response to disease or injury may be maladaptive. More specifically, imbalance among TrkB receptor isoforms appears to contribute to aberrant signaling and hyperpathic pain. A truncated isoform of the receptor, TrkB.T1, lacks the intracellular kinase domain of the full length receptor and is up-regulated in multiple CNS injury models. Such up-regulation is associated with hyperpathic pain, and TrkB.T1 inhibition reduces neuropathic pain in various experimental paradigms. Deletion of TrkB.T1 also limits astrocyte changes in vitro, including proliferation, migration, and activation. Mechanistically, TrkB.T1 is believed to act through release of intracellular calcium in astrocytes, as well as through interactions with neurotrophins, leading to cell cycle activation. Together, these studies support a potential role for astrocytic TrkB.T1 in hyperpathic pain and suggest that targeted strategies directed at this receptor may have therapeutic potential.
Learn More >Single nucleotide polymorphisms (SNPs) of the voltage-gated sodium channel alpha subunit gene (SCN9A) have been associated with pain in various settings. The aim of this study was to investigate the association of the SNPs to evaluate the influence of common gene variants on chronic postoperative pain (CPSP) and other related pain variables in a cohort of patients who underwent a scheduled hysterectomy.
Learn More >Epoxyeicosatrienoic acids (EET) and related epoxy fatty acids (EpFA) are endogenous anti-inflammatory compounds, which are converted by the soluble epoxide hydrolase (sEH) to dihydroxylethersatrienoic acids (DHETs) with lessened biological effects. Inhibition of sEH is used as a strategy to increase EET levels leading to lower inflammation. Rheumatoid arthritis is a chronic autoimmune disease that leads to destruction of joint tissues. This pathogenesis involves a complex interplay between the immune system, and environmental factors. Here, we investigate the effects of inhibiting sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) on a collagen-induced arthritis model. The treatment with TPPU ameliorates hyperalgesia, edema, and decreases the expression of important pro-inflammatory cytokines of Th1 and Th17 profiles, while increasing Treg cells. Considering the challenges to control RA, this study provides robust data supporting that inhibition of the sEH is a promising target to treat arthritis.
Learn More >Complex Regional Pain Syndrome (CRPS) is a poorly understood chronic pain condition of multifactorial origin. CRPS involves sensory, motor, and autonomic symptoms primarily affecting one extremity. Patients can also present with neuropsychological changes such as reduced attention to the CRPS-affected extremity, reminiscent of hemispatial neglect, yet in the absence of any brain lesions. However, this "neglect-like" framework is not sufficient to characterise the range of higher cognitive functions that can be altered in CRPS. This comprehensive literature review synthesises evidence of neuropsychological changes in CRPS in the context of potential central mechanisms of the disorder. The affected neuropsychological functions constitute three distinct but not independent groups: distorted body representation, deficits in lateralised spatial cognition, and impairment of non-spatially-lateralised higher cognitive functions. We suggest that many of these symptoms appear to be consistent with a broader disruption to parietal function beyond merely what could be considered "neglect-like." Moreover, the extent of neuropsychological symptoms might be related to the clinical signs of CRPS, and rehabilitation methods that target the neuropsychological changes can improve clinical outcomes in CRPS and other chronic pain conditions. Based on the limitations and gaps in the reviewed literature, we provide several suggestions to improve further research on neuropsychological changes in chronic pain.
Learn More >The analysis of particular (electroencephalographic) EEG frequency bands has revealed new insights relative to the neural dynamics that, when studying the EEG spectrum as a whole, would have remained hidden. This study is aimed at characterizing spectral resting state EEG patterns for assessing possible differences of episodic and chronic migraine during the interictal period. For that purpose, a novel methodology for analyzing specific frequencies of interest was performed.
Learn More >Chronic pain can be the result of an underlying disease or condition, medical treatment, inflammation, or injury. The number of persons experiencing this type of pain is substantial, affecting upwards of 50 million adults in the United States. Pharmacotherapy of most of the severe chronic pain patients includes drugs such as gabapentinoids, re-uptake blockers and opioids. Unfortunately, gabapentinoids are not effective in up to two-thirds of this population and although opioids can be initially effective, their long-term use is associated with multiple side effects. Therefore, there is a great need to develop novel non-opioid alternative therapies to relieve chronic pain. For this purpose, we screened a small library of natural products and their derivatives in the search for pharmacological inhibitors of voltage-gated calcium and sodium channels, which are outstanding molecular targets due to their important roles in nociceptive pathways. We discovered that the acetylated derivative of the ent-kaurane diterpenoid, geopyxin A, 1-O-acetylgeopyxin A, blocks voltage-gated calcium and tetrodotoxin-sensitive voltage-gated sodium channels but not tetrodotoxin-resistant sodium channels in dorsal root ganglion (DRG) neurons. Consistent with inhibition of voltage-gated sodium and calcium channels, 1-O-acetylgeopyxin A reduced reduce action potential firing frequency and increased firing threshold (rheobase) in DRG neurons. Finally, we identified the potential of 1-O-acetylgeopyxin A to reverse mechanical allodynia in a preclinical rat model of HIV-induced sensory neuropathy. Dual targeting of both sodium and calcium channels may permit block of nociceptor excitability and of release of pro-nociceptive transmitters. Future studies will harness the core structure of geopyxins for the generation of antinociceptive drugs.
Learn More >A highly potent, selective NaV1.7 inhibitor, DS-1971a has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives (I and II) led to the discovery of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile.
Learn More >Platinum-based chemotherapeutics still play an important role in cancer therapy, however, severe side effects, such as painful neuropathy, occur frequently. The pathophysiologic mechanisms depend on the applied chemotherapeutic agent and are still controversial. In addition to neuronal damage, disturbance of glial cell activity may contribute to neurotoxicity. Here, we focused on the effect of oxaliplatin on satellite glial cell (SGC) function and on the activity of the dorsal root ganglion (DRG) neurons. SGCs were isolated as high-purity cultures and treated with 1 and 10 μM oxaliplatin for 2, 4 and 24 h. Subsequently, glial fibrillary acid protein (GFAP), reactive oxygen species (ROS), Connexin-43 (Cx-43), and inward rectifier potassium channel 4.1 (K) expression was determined by immunocytochemical staining (ICC) and Western blot analyses. Immunochemical staining and Western blot analysis showed an increase in the immune reactivity (IR) and protein levels of ROS, GFAP, and Cx-43. Furthermore, reduction of the IR and protein levels and current density were demonstrated using patch-clamp measurements, of K channels after oxaliplatin exposure. Cytokine release in SGCs was measured using enzyme-linked immunosorbent assays (ELISA) after oxaliplatin exposure and indicated an increased release of IL-6 and TNFα, while IL-1β was decreased. The direct influence of SGC-secreted factors in the supernatant after oxaliplatin treatment led to the hyperexcitability of cultured DRG neurons. In summary, oxaliplatin has a direct impact on the modulation and function of different SGC proteins. Furthermore, SGC-released factors influence the excitability of sensory neurons, qualifying SGCs as potential targets for the prevention and treatment of oxaliplatin-induced polyneuropathy.
Learn More >First-degree relatives (FDR) of patients with rheumatoid arthritis (RA) have a higher risk for the development of RA. In the stages prior to the development of arthritis, nonspecific musculoskeletal (MSK) manifestations may occur. The aim of the study is to describe the frequency of rheumatic regional pain syndromes (RRPS) in FDR of RA patients. A cross-sectional study was carried out from July 2016 to September 2018. Parents, offspring, and siblings of RA patients completed the Community Oriented Program in the Rheumatic Diseases (COPCORD) questionnaire. Rheumatoid factor (RF) IgG, IgM, and IgA; anticitrullinated peptide antibodies (ACPAs); C-reactive protein (CRP); and erythrocyte sedimentation rate (ESR) were determined. All subjects with a positive COPCORD (defined by the presence of musculoskeletal pain) were evaluated and classified. Three hundred thirty-five FDRs participated, 75.8% were female, mean age of 44.15 years; 138 (41.2%) were diagnosed with at least one RRPS; 72 (21.5%) had rotator cuff tendinitis, 51 (15.2%) pes anserine bursitis, and 39 (11.6) lateral epicondylitis; RA was diagnosed in 24 (7.16%) subjects, undifferentiated arthritis (UA) in 30 (8.9%) and inflammatory arthralgia (AI) in 104 (31%). We found anti-CCP positivity in 6.8%, RF IgA in 22.3%, RF IgM in 48.6%, and RF IgG in 8.9%. The presence of RRPS was higher in this RA-FDR group compared to general population. Clinical evaluation of this risk group should include screening for RRPS.
Learn More >Natural or synthetic ligands for peroxisome proliferator-activated receptor gamma (PPAR-γ) represent an interesting tool for pharmacological interventions to treat inflammatory conditions. In particular, PPAR-γ activation prevents pain and inflammation in the temporomandibular joint (TMJ) by decreasing cytokine release and stimulating the synthesis of endogenous opioids. The goal of this study was to clarify whether PPAR-γ activation induces macrophage polarization, inhibiting inflammatory cytokine release and leukocyte recruitment. In addition, we investigated the involvement of heme oxygenase 1 (HO-1) in downstream events after PPAR-γ activation. Our results demonstrate that PPAR-γ activation ablates cytokine release by Bone Marrow-Derived Macrophages (BMDM) in vitro. 15d-PGJ induces the PPAR-γ heterodimer activation from rat macrophages, with macrophage polarization from M1-like cells toward M2-like cells. This response is mediated through HO-1. PPAR-γ activation diminished neutrophil migration induced by carrageenan, which was also HO-1 dependent. Ca/calmodulin expression did not change after PPAR-γ activation indicating that is not required for the activation of the intracellular L-arginine/NO/cGMP/K channel pathway. In summary, the anti-inflammatory actions induced by PPAR-γ activation involve macrophage polarization. HO-1 expression is increased and HO-1 activity is required for the suppression of neutrophil migration.
Learn More >One of the most prevalent symptoms after major surgery is pain. When postoperative pain treatment is unsatisfactory, it can lead to poor surgical recovery, decreased quality of life, and increased health care costs. Current analgesics, single or in combination, have limited efficacy due to low potency, limited duration of action, toxicities, and risk of addiction. The lack of nonaddictive strong analgesics along with the over prescription of opioids has led to an opioid epidemic in the United States. Therefore, there is an urgent need for the development of newer analgesics. Microribonucleic acids (miRNAs) are small noncoding RNA molecules that modulate protein synthesis in neurons and supporting cells (glia, leukocytes, and Schwann cells). The literature indicates that miRNA regulation is important in nociception. Here, we summarize the current evidence on the role of miRNAs on mechanisms involved in incisional, inflammatory, neuropathic, and cancer pain. We also discuss the role of modulating miRNA functions as potential therapeutic targets for analgesic use and opioid tolerance. Finally, we propose how the delivery of analog miRNAs (mimic-miRNAs or antago-miRNAs) could be introduced into clinical practice to provide analgesia in the perioperative period.
Learn More >Despite similar distribution patterns and intracellular events observed in the nociceptin/orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and non-peptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptorrelated ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.
Learn More >Background and aims Although several studies have been conducted, knowledge about chronic pain and dyspareunia after childbirth is still limited. The aim of this study was to explore the prevalence of chronic pain 8 months after childbirth in a cohort of Swedish women. The characteristics of chronic pain, such as, pain intensity, localization and frequency as well as pain interference with daily activities were examined. An additional aim was to describe the prevalence and intensity of dyspareunia. Methods Data were obtained through two self-administered questionnaires and the patient record system, Obstetrix. The first questionnaire was distributed on the maternity ward, 24-36 h after labour, to Swedish-speaking women who had given birth to a living child (n = 1,507). The second questionnaire was sent by post 8 months after childbirth. We collected data about demographic and social characteristics, pain presence and its onset, as well as pain intensity, frequency, bodily localization and pain interference with activities of women's daily life. Results In total, 1,171 (77.7%) responded to both questionnaires and were included in the analysis. Eight months after giving birth, totally 16.7% (195/1,171) of the women reported chronic pain related to childbirth. Of these, 9.1% (106/1,171) of women reported chronic pain with onset during pregnancy, 4.5% (53/1,171) experienced chronic pain with onset following labour and 3.1% (36/1,171) of women had both chronic pain with onset during pregnancy and chronic pain with onset following labour (each participant could only appear in one of the groups). Women reported a lower prevalence of chronic pain after vaginal delivery than caesarean section (61/916, 6.7% vs. 28/255, 11%, p = 0.021, OR 1.73, 95% CI 1.1-2.8). Moreover, 19.2% (211/1,098) of women experienced dyspareunia. There was no difference regarding prevalence of dyspareunia and the mode of delivery. Of those women who had a vaginal delivery, 19.5% (167/858) experienced pain during intercourse and the corresponding number for women after caesarean section was 18.3% (44/240) (p = 0.694, OR 0.929, CI 0.6-1.3). Approximately 80% of women with chronic pain, and 60% of women that experienced dyspareunia, rated their worst pain as moderate or severe (NRS 4-10). The corresponding number regarding average chronic pain was between 50 and 70%. More than 35% of the women with chronic pain scored pain interference with daily activities as ≥4 on a 0-10 NRS. Conclusions In our study, chronic pain 8 months after childbirth was reported by one in six women and one in five of the women experienced dyspareunia. The intensity of both chronic pain and dyspareunia was reported as moderate to severe in a significant proportion of women and chronic pain interfered considerably with daily activities. Implications There is a need to raise awareness among healthcare providers of this clinical problem as well as to revise and upgrade education regarding pain after childbirth to prevent potential long-term health problems, women's suffering and increased need for health care. The development of strategies for prevention, follow-up and treatment of pain is warranted. More research, including women's experiences of pain as well as intervention studies, are also needed.
Learn More >The Pain Catastrophizing Scale (PCS) is a widely used self-report tool to evaluate pain related catastrophizing. The PCS was developed using classical test theory and has been shown to be psychometrically sound among various populations. However, it's current three subscales are rarely used in clinical practice, offering potential for an abbreviated version that reduces administrative burden and can be used to estimate full scale scores, yet is not bound by the inclusion of items from each subscale. Hence, the aim of the current study was to develop a unidimensional abbreviated version of the PCS through findings from qualitative, classical test theory, and newer Rasch analysis.
Learn More >The aim of this study was to uncover possible psychosocial underpinnings of pain and sleep disturbance in a safety-net primary care sample.
Learn More >This quality improvement project was implemented in order to highlight the association between headache, mTBI and depression on lost productivity and resource utilization.
Learn More >Migraine, and especially migraine with aura, is associated with an increased risk of stroke and vascular events; however, the reasons for this association are unclear. Several studies evaluated cerebral autoregulation and vasomotor reactivity in patients with migraine compared with non-migraineurs, with conflicting results. Our narrative review aimed at summarizing their results to find the most reliable evidence in the field. Studies which used visual stimuli to evoke vascular responses consistently showed an increased vascular reactivity in migraineurs compared with non-migraineurs, while studies which used systemic stimuli such as hyper- or hypocapnia showed inconsistent results. Therefore, central neural mechanisms might be more important than peripheral vascular mechanisms in determining the cerebral vascular responses of patients with migraine. However, a large body of evidence supports the existence of peripheral vascular dysfunction in patients with migraine. Further studies are needed to explain the complex interactions between central neural and peripheral vascular mechanisms in determining migraine and its vascular risk. Migraine preventive treatments, and especially the most recent ones with a peripheral action, might provide important insights in this field.
Learn More >Over 70% to 85% of men with advanced prostate cancer (PCa) develop bone metastases characterized by severe bone pain and increased likelihood of bone fracture. These clinical features result in decreased quality of life and act as a predictor of higher mortality. Mechanistically, the skeletal pathologies such as osteolytic lesions and abnormal osteoblastic activity drive these symptoms. The role of immune cells in bone cancer pain remains understudied, here we sought to recapitulate this symptomology in a murine model.
Learn More >Paclitaxel treatment is a major cause of chemotherapy-induced peripheral neuropathy. The sodium channel Nav1.7 plays a critical role in pain perception. However, whether Nav1.7 in the dorsal root ganglion (DRG) is involved in paclitaxelinduced peripheral neuropathy remains unclear. Thus, our study aimed to evaluate whether Nav1.7 participates in the pathogenesis of paclitaxel-induced neuropathy.
Learn More >To evaluate the national general prevalence of postoperative pain and the associated organizational/structural factors related to the provision of health care services.
Learn More >To define the characteristics of post-traumatic headache with cluster headache phenotype (PTH-CH) and to compare these characteristics with primary CH.
Learn More >The goal of this study was to examine the associations among posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), sleep quality, pain interference, and quality of life in combat veterans.
Learn More >To examine the effectiveness of intensive interdisciplinary pain treatment for improving disability in children with chronic headache using the International Classification of Functioning, Disability and Health model as a conceptual framework for disability assessment. Children with chronic headache ( = 50; ages 10-19 years; 62% female) attended an intensive interdisciplinary pain treatment program 8 h/day, 5 times/week for 2-7 weeks. Disability measures were administered at admission, discharge, and 6-8 week follow-up. Disability outcomes were analyzed retrospectively. Wilcoxon signed rank tests and Friedman's analyses of variance were used to compare scores across two and three longitudinal time points, respectively. After rehabilitation, disability reduced on the Headache Impact Test-6 from severe impact at admission to some impact at follow-up ( < 0.001). Median time on the modified Bruce protocol increased from 13.1 min (interquartile range = 12.6-14.1) to 14.4 min (interquartile range = 12.9-16.3), < 0.001, with gains maintained at follow-up. Improvements in pain and disability were associated with improvements in school participation. Findings of this study support the effectiveness of intensive interdisciplinary pain treatment for improving disability in children with chronic headache.Implication for rehabilitationIntensive interdisciplinary pain treatment is effective for improving pain and disability in children with chronic headaches.Application of the ICF model to disability assessment suggests that children with chronic headaches may experience significant disability, even when standardized assessments of physical capacity are normal.The modified Bruce protocol, Pediatric Evaluation of Disability Inventory – Computerized Adaptive Tests, and Headache Impact Test-6 appear particularly valuable in understanding the nature of disability in children with chronic headaches.
Learn More >Approximately 35%-50% of people with haemophilia (PWH) report living with chronic musculoskeletal pain. Although exercise based rehabilitation is effective for pain in other arthritises, there are no published guidelines for management of chronic pain in PWH. This review aims to evaluate and appraise the current evidence of effectiveness of physiotherapy interventions on (a) pain intensity, (b) quality of life (QoL) and (c) function in PWH.
Learn More >Adult migraine remains underdiagnosed and undertreated, despite significant negative effects on physical and emotional functioning. Information on prescribing patterns and treatment costs of migraine in China is limited.
Learn More >Several studies have shown that oral sucrose reduces pain in newborns. However, sucrose has no efficacy in eliminating pain and long-term effects remain unclear. Breast milk may be useful as an alternative, safe sweet solution. Sensorial saturation (SS) is a multisensory analgesic non-pharmacological treatment, which includes touch and sounds as distractors. This study aimed to compare the analgesic effects of SS with sucrose (SSS), SS with breast milk (SSB), and oral sucrose alone (S24%) in neonates undergoing venipuncture.
Learn More >To describe the efficacy of tofacitinib in reducing pain in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS) in a post-hoc analysis of randomised controlled trials.
Learn More >Adults with sleep problems are at higher risk for onset of musculoskeletal pain, but the evidence is less clear for children. This prospective cohort study investigated whether children with sleep problems are at higher risk for onset of musculoskeletal pain and explored whether sex is a modifier of this association. In a prospective cohort study of Australian schoolchildren (n = 1239, mean age 9 years), the associations between sleep problems at baseline and new onset of both musculoskeletal pain and persistent musculoskeletal pain (pain lasting > 3 months) 1 year later were investigated using logistic regression. The potential modifying effect of sex was also assessed. One-year incidence proportion for musculoskeletal pain onset is 43% and 7% for persistent musculoskeletal pain. Sleep problems were associated with musculoskeletal pain onset and persistent musculoskeletal pain onset in boys, odds ratio 2.80 (95% CI 1.39, 5.62) and OR 3.70 (1.30, 10.54), respectively, but not girls OR 0.58 (0.28, 1.19) and OR 1.43 (0.41, 4.95), respectively.Conclusions: Rates of musculoskeletal pain are high in children. Boys with sleep problems are at greater risk of onset of musculoskeletal pain, but girls do not appear to have higher risk. Consideration of sleep health may help prevent persistent musculoskeletal pain in children.What is Known:• Sleep problems are associated with the onset of musculoskeletal pain in adults.• It is not clear if the association between sleep problems and the onset of musculoskeletal pain is present also in children and if sex plays a role in this association.What is New:• This is the first large population-based study that has prospectively investigated the relationship between sleep problems and onset of musculoskeletal pain in school-aged children.• Children, especially boys with sleep problems, were at increased risk for the development of persistent musculoskeletal pain.
Learn More >Neuroinflammation plays a vital role in the development and maintenance of neuropathic pain. Recent evidence has proved that bone marrow mesenchymal stem cells (BMSCs) can inhibit neuropathic pain and possess potent immunomodulatory and immunosuppressive properties via secreting a variety of bioactive molecules, such as TNF-α-stimulated gene 6 protein (TSG-6). However, it is unknown whether BMSCs exert their analgesic effect against neuropathic pain by secreting TSG-6. Therefore, the present study aimed to evaluate the analgesic effects of TSG-6 released from BMSCs on neuropathic pain induced by chronic constriction injury (CCI) in rats and explored the possible underlying mechanisms in vitro and in vivo.
Learn More >Headache sufferers in need of professional health care often do not utilize the care available, and factors influencing headache-specific physician consultation are not yet understood. Objectives of this study are (1) to assess self-reported headache-specific physician consultations and (2) to identify headache-related and sociodemographic predictors.
Learn More >Low back pain is a prevalent condition that causes a substantial health burden. Despite intensive and expensive clinical efforts, its prevalence is growing. Nonpharmacologic treatments are effective at improving pain-related outcomes; however, treatment effect sizes are often modest. Physical therapy (PT) and cognitive behavioral therapy (CBT) have the most consistent evidence of effectiveness. Growing evidence also supports mindfulness-based approaches. Discussions with providers and patients highlight the importance of discussing and trying options to find the treatment that works for them and determining what to do when initial treatment is not successful. Herein, we present the protocol for a study that will evaluate evidence-based, protocol-driven treatments using PT, CBT, or mindfulness to examine comparative effectiveness and optimal sequencing for patients with chronic low back pain.
Learn More >Liquiritin Alleviates Pain Through Inhibiting CXCL1/CXCR2 Signaling Pathway in Bone Cancer Pain Rat.
Bone cancer pain (BCP) is an intractable clinical problem, and lacked effective drugs for treating it. Recent research showed that several chemokines in the spinal cord are involved in the pathogenesis of BCP. In this study, the antinociceptive effects of liquiritin, which is an active component extracted from Glycyrrhizae Radix, were tested and the underlying mechanisms targeting spinal dorsal horn (SDH) were investigated. The BCP group displayed a significant decrease in the mechanical withdrawal threshold on days 6, 12, and 18 when compared with sham groups. Intrathecal administration of different doses of liquiritin alleviated mechanical allodynia in BCP rats. The results of immunofluorescent staining and western blotting showed that liquiritin inhibited BCP-induced activation of astrocytes in the spinal cord. Moreover, intrathecal administration of liquiritin effectively inhibited the activation of CXCL1/CXCR2 signaling pathway and production of IL-1β and IL-17 in BCP rats. In astroglial-enriched cultures, Lipopolysaccharides (LPS) elicited the release of chemokine CXCL1, and the release was decreased in a dose-dependent manner by liquiritin. In primary neurons, liquiritin indirectly reduced the increase of CXCR2 by astroglial-enriched-conditioned medium but not directly on the CXCR2 target site. These results suggested that liquiritin effectively attenuated BCP in rats by inhibiting the activation of spinal astrocytic CXCL1 and neuronal CXCR2 pathway. These findings provided evidence regarding the the antinociceptive effect of liquiritin on BCP.
Learn More >Stigma is associated with many health conditions, including chronic pain. Research on health-related stigma is limited by the lack of validated instruments that distinguish among various stigma-related constructs. We aimed to develop and validate such a measure for pediatric functional abdominal pain (FAP). Felt stigma (FS) was defined as comprising both perceived and internalized stigma. Stigma concealment (SC) was defined as efforts by stigmatized individuals to prevent others from learning of their condition.
Learn More >Previous case-control investigations of type I Chiari malformation (CMI) have reported cognitive deficits and microstructural white matter abnormalities, as measured by diffusion tensor imaging (DTI). CMI is also typically associated with pain, including occipital headache, but the relationship between pain symptoms and microstructure is not known.
Learn More >Chronic pelvic pain in women is a complex condition, and physical therapy is recommended as part of a broader treatment approach. The objective of this study was to compare structured group-based multimodal physical therapy in a hospital setting (intervention group) with primary care physical therapy (comparator group) for women with chronic pelvic pain.
Learn More >The mechanisms underlying type-2 diabetic neuropathic pain (DNP) are unclear. This study investigates the coupling of postsynaptic density-95 (PSD-95) to N-methyl-D-aspartate receptor subunit 2B (GluN2B), and the subsequent phosphorylation of GluN2B (Tyr1472-GluN2B) in the spinal cord in a rat model of type-2 DNP. Expression levels of PSD-95, Tyr1472-GluN2B, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its phosphorylated counterpart (Thr286-CaMKII), and α-amino-3-hydroxy-5-methyl-4-soxazole propionic acid receptor subtype 1 (GluR1) and its phosphorylated counterpart (Ser831-GluR1) were significantly increased versus controls in the spinal cord of type-2 DNP rats whereas the expression of total spinal GluN2B did not change. The intrathecal injection of Ro25-6981 (a specific antagonist of GluN2B) or Tat-NR2B9c (a mimetic peptide disrupting the interaction between PSD-95 and GluN2B) induced an antihyperalgesic effect and blocked the increased expression of Tyr1472-GluN2B, CaMKII, GluR1, Thr286-CaMKII, and Ser831-GluR1 in the spinal cords; the increase in spinal cord PSD-95 was not affected. These findings indicate that the PSD-95-GluN2B interaction may increase phosphorylation of GluN2B, and subsequently induce the expression of phosphorylation of CaMKII and GluR1 in the spinal cord of type-2 DNP rats. Targeting the interaction of PSD-95 with GluN2B may provide a new therapeutic strategy for type-2 DNP.
Learn More >Subjective cognitive dysfunction is common among migraineurs. The aim of this review is to evaluate the usefulness of psychophysiology by means of the P300 component of the event-related potential in the understanding of subtle and sub-clinical changes in cognition that may occur during and between migraine episodes. Some P300 studies suggest a potential impairment of information processing, as reflected by only few findings of interictal decreased amplitude and prolonged latency, ictal augmented amplitude and prolonged latency, changes in cognitive habituation, and limited capacity to relocate attention away from painful stimuli. P300 may represent a valuable aid for clinicians to identify patients at risk of chronicization and cognitive weakening due to neurovascular complications; in this perspective a research agenda may be planned involving larger numbers of patients undergoing psychophysiological studies.
Learn More >One of the consequences of the opioid epidemic is an increase in the number of opioid-tolerant patients. These patients are at higher risk for readmission and longer hospital stays following surgery. Enhanced recovery after surgery (ERAS) pathways can be used as a framework for providing high-quality comprehensive care to patient population. It is estimated that as many as 15% of all surgery patients in the USA are receiving opioids going into surgery. The number of patients on medication maintenance therapy with long-acting opioids such as methadone or partial mu receptor agonists like buprenorphine is rising, which poses a challenge for perioperative healthcare providers.
Learn More >Thirty patients (60%) found it satisfying or very satisfying to communicate their pain with the app. Pain experienced after surgery was scored by patients as 'no': 3 (6%), 'little': 5 (10%), 'bearable': 25 (50%), 'considerable': 13 (26%) and 'severe': 1 (2%). Forty-five patients (90%) were positive about the ease of recording. Forty-five patients (90%) could correctly record their pain with the app. Thirty-eight patients (76%) agreed that in-app notifications to record pain were useful. Two patients (4%) were too ill to use the application. Based on usability feedback, we will redesign the pain intensity wheel and the in-app pain chart to improve clarity for patients to understand the course of their pain.
Learn More >Chronic pain in adolescents can be highly impairing. Parental reactions to their child's pain are important factors influencing pain perception and pain-related impairment in children and adolescents. The present study aimed to examine parental accommodation of pain symptoms using the Inventory of Parent Accommodations of Children's Symptoms (IPACS) to provide empirical support for the utility of this measure in parents of adolescents with chronic pain. We examined the prevalence, nature, and correlates of accommodation behaviors in 66 adolescents with chronic pain and their parents using the IPACS. All parents reported some level of accommodation of their child's pain symptoms. After controlling for pain severity, parental accommodation was associated with functional impairment. In addition, parental accommodation mediated the link between parental catastrophizing reactions to pain and child impairment and between child anxiety and depressive symptoms and child impairment. The IPACS appears to be a useful measure of parental accommodation of pain. Parental accommodation should be included as an intervention target when necessary. It is important to educate families about the negative consequences that can be related to excessive accommodation of pain symptoms and to provide effective resources to manage the impact of chronic pain and replace accommodation with more adaptive pain coping strategies.
Learn More >Cluster headache is a rare form of headache associated with sleep and even speculated to be a manifestation of a sleep disorder rather than a primary headache. Cluster headache exhibits both circadian and circannual rhythmicity. While attacks often occur during sleep, the implication that cluster headaches might be involved with rapid eye movement (REM) sleep phases has neither been fully established nor refuted. The regulatory mechanisms governing sleep including hypothalamic activity and the autonomic nervous system response may play a role. Hypothalamic activation has been observed in cluster headache patients during positron emission tomography testing, but only during attacks. While sleep apnea is associated with morning headaches in general, the link between sleep-disordered respiration and cluster headache remains elusive. Hypoarousal during sleep and periods of hypoxia are associated with cluster headache, the latter likely involving inflammatory processes rather than apnea. Further study is needed, as cluster headaches represent a serious primary cephalgia that is incompletely understood.
Learn More >Measuring health-related quality of life (HRQOL) in patients with chronic low back pain (LBP) is crucial to monitor and improve the patients' health status through effective rehabilitation. While the 12-item short-form health survey (SF-12) was developed as a shorter alternative to the 36-item short-form health survey for assessing HRQOL in large-scale studies, to date, no cross-culturally adapted and validated Hausa version exists. This study aimed to translate and cross-culturally adapt the SF-12 into Hausa language, and test its psychometric properties in mixed urban and rural Nigerian populations with chronic LBP.
Learn More >Targeted Drug Delivery (TDD) is commonly used for the management of patients with intractable pain. Past studies have proven efficacy in pain relief and reduction in opioid use and cost-effectiveness in long-term pain management. There are few studies investigating satisfaction among patients with implanted pain pumps that are managed with targeted intrathecal medications.
Learn More >Migraine is common and ranked as the first cause of disability in people under fifty. Despite significant advances in its pharmacological treatment, it often remains intractable. Neuromodulation is one option considered in the management of those patients.
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