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Papers: 30 Apr 2022 - 6 May 2022

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Neuronal pentraxin 2 is required for facilitating excitatory synaptic inputs onto spinal neurons involved in pruriceptive transmission in a model of chronic itch.

An excitatory neuron subset in the spinal dorsal horn (SDH) that expresses gastrin-releasing peptide receptors (GRPR) is critical for pruriceptive transmission. Here, we show that glutamatergic excitatory inputs onto GRPR neurons are facilitated in mouse models of chronic itch. In these models, neuronal pentraxin 2 (NPTX2), an activity-dependent immediate early gene product, is upregulated in the dorsal root ganglion (DRG) neurons. Electron microscopy reveals that NPTX2 is present at presynaptic terminals connected onto postsynaptic GRPR neurons. NPTX2-knockout prevents the facilitation of synaptic inputs to GRPR neurons, and repetitive scratching behavior. DRG-specific NPTX2 expression rescues the impaired behavioral phenotype in NPTX2-knockout mice. Moreover, ectopic expression of a dominant-negative form of NPTX2 in DRG neurons reduces chronic itch-like behavior in mice. Our findings indicate that the upregulation of NPTX2 expression in DRG neurons contributes to the facilitation of glutamatergic inputs onto GRPR neurons under chronic itch-like conditions, providing a potential therapeutic target.

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Chronic pain recruits hypothalamic dynorphin/kappa opioid receptor signalling to promote wakefulness and vigilance.

Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep disruption enhances pain, but the underlying mechanisms remain unknown. Chronic pain engages brain stress circuits and increases secretion of dynorphin, an endogenous ligand of the kappa opioid receptor (KOR). We therefore hypothesized that hypothalamic dynorphin/KOR signaling may be a previously unknown mechanism that is recruited in pathological conditions requiring increased vigilance. We investigated the role of KOR in wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in freely moving naïve mice and in mice with neuropathic pain induced by partial sciatic nerve ligation (PSNL) using EEG/EMG recordings. Systemic continuous administration of U69,593, a KOR agonist, over 5 days through an osmotic minipump decreased the amount of NREM and REM sleep and increased sleep fragmentation in naive mice throughout the light-dark sleep cycle. We used KORcre mice to selectively express a Gi-coupled designer receptor activated by designer drugs (Gi-DREADD) in KORcre neurons of the hypothalamic paraventricular nucleus (PVN), a key node of the hypothalamic-pituitary-adrenal (HPA) stress response. Sustained activation of Gi-DREADD with clozapine-N-oxide (CNO) delivered in drinking water over 4 days disrupted sleep in these mice in a similar way as systemic U69,593. Mice with chronic neuropathic pain also showed disrupted NREM and total sleep that was normalized by systemic administration of two structurally different KOR antagonists, norbinaltorphimine (nor-BNI) and NMRA-140, currently in phase II clinical development, or by CRISPR/Cas9 editing of PVN KOR, consistent with endogenous KOR activation disrupting sleep in chronic pain. Unexpectedly, REM sleep was diminished by either systemic KOR antagonist or by CRISPR/Cas9 editing of PVN KOR in sham-operated mice. Our findings reveal previously unknown physiological and pathophysiological roles of dynorphin/KOR in eliciting arousal. Physiologically, dynorphin/KOR signaling affects transitions between sleep stages that promote REM sleep. Furthermore, while KOR antagonists do not promote somnolence in the absence of pain, they normalized disrupted sleep in chronic pain, revealing a pathophysiological role of KOR signaling that is selectively recruited to promote vigilance, increasing chances of survival. Notably, while this mechanism is likely beneficial in the short-term, disruption of the homeostatic need for sleep over longer periods may become maladaptive resulting in sustained pain chronicity. A novel approach for treatment of chronic pain may thus result from normalization of chronic pain-related sleep disruption by KOR antagonism.

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E74-like factor 1 contributes to nerve trauma-induced nociceptive hypersensitivity via transcriptionally activating matrix metalloprotein-9 in dorsal root ganglion neurons.

Nerve trauma-induced alternations of gene expression in the neurons of dorsal root ganglion (DRG) participate in nerve trauma-caused nociceptive hypersensitivity. Transcription factors regulate gene expression. Whether the transcription factor E74-like factor 1 (ELF1in the DRG contributes to neuropathic pain is unknown. We report here that peripheral nerve trauma caused by chronic constriction injury (CCI) of unilateral sciatic nerve or unilateral fourth lumbar spinal nerve ligation led to the time-dependent increases in the levels of Elf1 mRNA and ELF1 protein in injured DRG, but not in spinal cord. Preventing this increase through DRG microinjection of adeno-associated virus 5-expressing Elf1 shRNA attenuated the CCI-induced upregulation of matrix metallopeptidase 9 (MMP9) in injured DRG and induction and maintenance of nociceptive hypersensitivities, without changing locomotor functions and basal responses to acute mechanical, heat and cold stimuli. Mimicking this increase through DRG microinjection of AAV5-expressing full-length Elf1 upregulated DRG MMP9 and produced enhanced responses to mechanical, heat and cold stimuli in naïve mice. Mechanistically, more ELF1 directly bond to and activated Mmp9 promoter in injured DRG neurons following CCI. Our data indicate that ELF1 participates in nerve trauma-caused nociceptive hypersensitivity likely through upregulating MMP9 in injured DRG. ELF1 may be a new target for management of neuropathic pain.

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Sensory neuron expressed TRPC3 mediates acute and chronic itch.

Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represent a huge unmet health problem. However, its underlying cellular and molecular mechanisms remain largely unexplored. TRPC3 is highly expressed in primary sensory neurons and has been implicated in peripheral sensitization induced by proinflammatory mediators. Yet, the role of TRPC3 in acute and chronic itch is still not well defined. Here, we show that, among mouse trigeminal ganglion (TG) neurons, Trpc3 mRNA is predominantly expressed in nonpeptidergic small diameter TG neurons of mice. Moreover, Trpc3 mRNA signal was present in the majority of presumptively itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch- and pain-like behaviors in naïve mice. In addition, genetic deletion of Trpc3 attenuated acute itch evoked by certain common nonhistaminergic pruritogens, including endothelin-1 and SLIGRL-NH2. In a murine model of contact hypersensitivity (CHS), Trpc3 mRNA expression level and function were upregulated in the TG following CHS. Pharmacological inhibition and global knockout of Trpc3 significantly alleviated spontaneous scratching behaviors without affecting concurrent cutaneous inflammation in the CHS model. Furthermore, conditional deletion of Trpc3 in primary sensory neurons but not in keratinocytes produced similar antipruritic effects in this model. These findings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch via a histamine independent mechanism and that targeting neuronal TRPC3 might benefit the treatment of chronic itch associated with ACD and other inflammatory skin disorders.

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Differentiation of iPS-Cells into Peripheral Sensory Neurons.

Induced pluripotent stem cells (iPS-cells) have significantly expanded our experimental possibilities, by creating new strategies for the molecular study of human disease and drug development. Treatment of pain has not seen much improvement over the past decade, likely due to species differences in preclinical models. Thus, iPS-cell derived sensory neurons offer a highly welcome translational approach for research and drug development. Although central neuronal differentiation is relatively straightforward, the successful and reliable generation of peripheral neurons requires more complex measures. Here, we describe a small molecule-based protocol for the differentiation of human sensory neurons from iPS-cells which renders functional nociceptor-like cells within several weeks.

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Estimates of Probabilities of Successful Development of Pain Medications: An Analysis of Pharmaceutical Clinical Development Programs 2000-2020.

We estimate the probability of successful development and duration of clinical trials for medications to treat neuropathic and nociceptive pain. We also consider the effect of the perceived abuse potential of the medication on these variables.

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Dual HDAC/BRD4 Inhibitors Relieves Neuropathic Pain by Attenuating Inflammatory Response in Microglia After Spared Nerve Injury.

Despite the effort on developing new treatments, therapy for neuropathic pain is still a clinical challenge and combination therapy regimes of two or more drugs are often needed to improve efficacy. Accumulating evidence shows an altered expression and activity of histone acetylation enzymes in chronic pain conditions and restoration of these aberrant epigenetic modifications promotes pain-relieving activity. Recent studies showed a synergistic activity in neuropathic pain models by combination of histone deacetylases (HDACs) and bromodomain and extra-terminal domain (BET) inhibitors. On these premises, the present study investigated the pharmacological profile of new dual HDAC/BRD4 inhibitors, named SUM52 and SUM35, in the spared nerve injury (SNI) model in mice as innovative strategy to simultaneously inhibit HDACs and BETs. Intranasal administration of SUM52 and SUM35 attenuated thermal and mechanical hypersensitivity in the absence of locomotor side effects. Both dual inhibitors showed a preferential interaction with BRD4-BD2 domain, and SUM52 resulted the most active compound. SUM52 reduced microglia-mediated spinal neuroinflammation in spinal cord sections of SNI mice as showed by reduction of IBA1 immunostaining, inducible nitric oxide synthase (iNOS) expression, p65 nuclear factor-κB (NF-κB) and p38 MAPK over-phosphorylation. A robust decrease of the spinal proinflammatory cytokines content (IL-6, IL-1ß) was also observed after SUM52 treatment. Present results, showing the pain-relieving activity of HDAC/BRD4 dual inhibitors, indicate that the simultaneous modulation of BET and HDAC activity by a single molecule acting as multi-target agent might represent a promise for neuropathic pain relief.

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A ketogenic diet prevents methylglyoxal-evoked nociception by scavenging methylglyoxal.

Methylglyoxal is a reactive dicarbonyl byproduct of glycolysis implicated in a growing number of neuropathic pain conditions, including chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, and radiculopathy with lumbar disc herniation. Recent studies show success in preclinical models treating these disorders with an interventional ketogenic diet. Here, we tested the hypothesis that a ketogenic diet modifies pathological methylglyoxal signaling as a mechanism underlying neuropathy improvement. We found that mice injected with methylglyoxal displayed nociceptive behaviors, whereas mice pre-fed a ketogenic diet were resistant to mechanical allodynia elicited by methylglyoxal. In addition, levels of circulating methylglyoxal were reduced in ketogenic diet-fed mice and negatively correlated with levels of the ketone body β-hydroxybutyrate. Methylglyoxal is normally scavenged by the glyoxalase system, and ketogenic diet-fed mice displayed increased glyoxalase 1 activity compared to chow-fed control mice. Recent studies also suggest ketone bodies contribute to methylglyoxal detoxification, consistent with negative correlation between β-hydroxybutyrate and methylglyoxal. To assess whether ketone bodies modified methylglyoxal-evoked nociception via direct methylglyoxal detoxification, we coincubated either acetoacetate or β-hydroxybutyrate with methylglyoxal prior to injection. Mice receiving intraplantar methylglyoxal injection exhibit increased nociceptive behavior (lifting, licking, biting, scratching), which was significantly reduced by coincubation with either acetoacetate or β-hydroxybutyrate. Methylglyoxal increased phospho-ERK-positive cells in the spinal dorsal horn, and this evoked spinal activation was ameliorated by preincubation with acetoacetate or β-hydroxybutyrate. These results suggest that a ketogenic diet and ketone bodies ameliorate methylglyoxal-evoked nociception, partially through detoxification of methylglyoxal, and provide rationale for therapeutic intervention with a ketogenic diet in methylglyoxal-driven pathologies.

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Gut Microbiome in Anesthesiology and Pain Medicine.

The gut microbiome plays critical roles in human health and disease. Recent studies suggest it may also be associated with chronic pain and postoperative pain outcomes. In animal models, the composition of the gut microbiome changes after general anesthesia and affects the host response to medications, including anesthetics and opioids. In humans, the gut microbiome is associated with the development of postoperative pain and neurocognitive disorders. Additionally, the composition of the gut microbiome has been associated with pain conditions including visceral pain, nociplastic pain, complex regional pain syndrome, and headaches, partly through altered concentration of circulating bacterial-derived metabolites. Furthermore, animal studies demonstrate the critical role of the gut microbiome in neuropathic pain via immunomodulatory mechanisms. This article reviews basic concepts of the human gut microbiome and its interactions with the host and provide a comprehensive overview of the evidence linking the gut microbiome to anesthesiology, critical care, and pain medicine.

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Opioid trends in Finland: a register-based nationwide follow-up study.

The opioid epidemic in the U.S has gotten payers, prescribers, and policymakers alike interested in trends in opioid use. Despite no recognized opioid crisis in Europe, several countries have reported an increase in opioid-related deaths, which has further prompted discussion on the need of monitoring of opioid prescriptions. This study was conducted to offer information on opioid use during the escalation of the U.S. opioid epidemic in Finland, a Nordic country with universal tax-based health care. This is a nationwide retrospective register-based cohort study on all individuals in Finland who were dispensed opioids in 2009-2017 (n of unique patients = 1,761,584). By using the unique personal identification code assigned to every Finnish resident, we linked data from nationwide registers on dispensed drugs, medical history, and socio-demographic parameters. We report a wide set of patient demographics, dispensing trends for all opioid Anatomical Therapeutic Chemical (ATC) classes, and reasons for opioid initiation based on diagnostic coding for the most recent health care visit. For a cohort of incident opioid users with a four-year wash-out period (n = 1 370 057), we also present opioid use patterns in a three-year follow-up: the likelihood of becoming a persistent user or escalating from weak to strong opioids. A steady 7% of the Finnish population were dispensed opioids annually in 2009-2017. The mean annual quantity of dispensed opioids per opioid patient increased between 2009 and 2017 by 33%, reaching 2 583 oral morphine equivalent mg (OMEQ)/patient/year in 2017. The median quantity of dispensed opioids was lower: 315 OMEQ/year/patient. Depending on the opioid ATC class, there were either increasing or decreasing numbers of patients who had been dispensed said opioid class, and also in the mean quantity. The most common reason for opioid initiation was post-surgical pain (20%), followed by musculoskeletal pain (15%), injury (8.3%), and non-postsurgical dental pain (6.2%). 94% of new opioid initiators started with a weak opioid, i.e. codeine or tramadol. 85% of the patients who had been dispensed a weak opioid were not dispensed an opioid subsequently 3-6 months after the first one, and 95% of them had not escalated to a strong opioid in a 3-year follow-up. The number of patients dispensed opioids in Finland did not change during the escalation of the opioid epidemic in the U.S., but there were changes in the quantity of opioids dispensed per patient. Opioid therapy was typically initiated with weak opioid, the initial dispensed prescription was relatively small, and escalation to strong opioids was rare. A considerable share of patients had been prescribed opioids for chronic non-cancer pain – a type of pain where the risk-benefit ratio of opioids is controversial.

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Mindfulness-Based Therapy Reduces Chronic Pain and Opioid Misuse.

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Dupilumab Provides Acceptable Safety and Sustained Efficacy for up to 4 Years in an Open-Label Study of Adults with Moderate-to-Severe Atopic Dermatitis.

Moderate-to-severe atopic dermatitis (AD) often requires long-term management with systemic therapies.

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Alike, but not quite: Comparing the generalization of pain-related fear and pain-related avoidance.

Pain-related fear and -avoidance crucially contribute to pain chronification. People with chronic pain may adopt costly avoidance strategies above and beyond what is necessary, aligning with experimental findings of excessive fear generalization to safe movements in these populations. Furthermore, recent evidence suggests that, when avoidance is costly, it can dissociate from fear. Here, we investigated whether concurrently measured pain-related fear and costly avoidance generalization correspond in one task. We also explored whether healthy participants avoid excessively despite associated costs, and if avoidance would decrease as a function of dissimilarity from a pain-associated movement. In a robotic arm-reaching task, participants could avoid a low-cost, pain-associated movement trajectory (T+), by choosing a high-cost non-painful movement trajectory (T-), at opposite ends of a movement plane. Subsequently, in the absence of pain, we introduced three movement trajectories (G1-3) between T+ and T-, and one movement trajectory on the side of T- opposite to T+ (G4), linearly increasing in costs from T+ to G4. Avoidance was operationalized as maximal deviation from T+, and as trajectory choice. Fear learning was measured using self-reported pain-expectancy, pain-related fear, and startle eye-blink EMG. Self-reports generalized, both decreasing with increasing distance from T+. In contrast, all generalization trajectories were chosen equally, suggesting that avoidance-costs and previous pain balanced each other out. No effects emerged in the EMG. These results add to a growing body of literature showing that (pain-related) avoidance, especially when costly, can dissociate from fear, calling for a better understanding of the factors motivating, and mitigating, disabling avoidance.

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Sensory testing and topical capsaicin can characterize patients with rheumatoid arthritis.

Our study aimed at examining the long-time inflammatory effects of rheumatoid arthritis (RA) as chronic immune-mediated disease on pain sensation and neuropathy development compared to healthy subjects (HS).

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Sex difference in disease burden of inflammatory arthritis patients treated with tumor necrosis factor inhibitors as part of standard care.

Knowledge is needed on the total disease burden across the sexes in inflammatory arthritis (IA). We aimed to compare disease burden, including a broad range of health aspects, across men and women with IA treated with tumor necrosis factor inhibitors (TNFi).

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Expert Consensus Regarding Core Outcomes for Enhanced Recovery after Cesarean Delivery Studies: A Delphi study.

Heterogeneity among reported outcomes from enhanced recovery after cesarean delivery impact studies is high. This study aimed to develop a standardized enhanced recovery core outcome set for use in future enhanced recovery after cesarean delivery studies.

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Regulation of clock and clock-controlled genes during morphine reward and reinforcement: Involvement of the period 2 circadian clock.

Morphine abuse is a devastating disorder that affects millions of people worldwide, and literature evidence indicates a relationship between opioid abuse and the circadian clock.

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Is the Sex Difference a Clue to the Pathomechanism of Dry Eye Disease? Watch out for the NGF-TrkA-Piezo2 Signaling Axis and the Piezo2 Channelopathy.

Dry eye disease (DED) is a multifactorial disorder with recognized pathology, but not entirely known pathomechanism. It is suggested to represent a continuum with neuropathic corneal pain with the paradox that DED is a pain-free disease in most cases, although it is regarded as a pain condition. The current paper puts into perspective that one gateway from physiology to pathophysiology could be a Piezo2 channelopathy, opening the pathway to a potentially quad-phasic non-contact injury mechanism on a multifactorial basis and with a heterogeneous clinical picture. The primary non-contact injury phase could be the pain-free microinjury of the Piezo2 ion channel at the corneal somatosensory nerve terminal. The secondary non-contact injury phase involves harsher corneal tissue damage with C-fiber contribution due to the lost or inadequate intimate cross-talk between somatosensory Piezo2 and peripheral Piezo1. The third injury phase of this non-contact injury is the neuronal sensitization process with underlying repeated re-injury of the Piezo2, leading to the proposed chronic channelopathy. Notably, sensitization may evolve in certain cases in the absence of the second injury phase. Finally, the quadric injury phase is the lingering low-grade neuroinflammation associated with aging, called inflammaging. This quadric phase could clinically initiate or augment DED, explaining why increasing age is a risk factor. We highlight the potential role of the NGF-TrkA axis as a signaling mechanism that could further promote the microinjury of the corneal Piezo2 in a stress-derived hyperexcited state. The NGF-TrkA-Piezo2 axis might explain why female sex represents a risk factor for DED.

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Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis.

Spasticity and chronic neuropathic pain are common and serious symptoms in people with multiple sclerosis (MS). These symptoms increase with disease progression and lead to worsening disability, impaired activities of daily living and quality of life. Anti-spasticity medications and analgesics are of limited benefit or poorly tolerated. Cannabinoids may reduce spasticity and pain in people with MS. Demand for symptomatic treatment with cannabinoids is high. A thorough understanding of the current body of evidence regarding benefits and harms of these drugs is required.

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Postoperative pain treatment after spinal fusion surgery: a systematic review with meta-analyses and trial sequential analyses.

Patients undergoing spinal surgery are at high risk of acute and persistent postoperative pain. Therefore, adequate pain relief is crucial. This systematic review aimed to provide answers about best-proven postoperative analgesic treatment for patients undergoing lumbar 1- or 2-level fusions for degenerative spine diseases. We performed a search in PubMed, Embase, and The Cochrane Library for randomized controlled trials. The primary outcome was opioid consumption after 24 hours postoperatively. We performed meta-analyses, trial sequential analyses, and Grading of Recommendations assessment to accommodate systematic errors. Forty-four randomized controlled trials were included with 2983 participants. Five subgroups emerged: nonsteroidal anti-inflammatory drugs (NSAIDs), epidural, ketamine, local infiltration analgesia, and intrathecal morphine. The results showed a significant reduction in opioid consumption for treatment with NSAID ( < 0.0008) and epidural ( < 0.0006) (predefined minimal clinical relevance of 10 mg). Concerning secondary outcomes, significant reductions in pain scores were detected after 6 hours at rest (NSAID [ < 0.0001] and intrathecal morphine [ < 0.0001]), 6 hours during mobilization (intrathecal morphine [ = 0.003]), 24 hours at rest (epidural [ < 0.00001] and ketamine [ < 0.00001]), and 24 hours during mobilization (intrathecal morphine [ = 0.03]). The effect of wound infiltration was nonsignificant. The quality of evidence was low to very low for most trials. The results from this systematic review showed that some analgesic interventions have the capability to reduce opioid consumption compared with control groups. However, because of the high risk of bias and low evidence, it was impossible to recommend a "gold standard" for the analgesic treatment after 1- or 2-level spinal fusion surgery.

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Symptoms reported by Canadians posted in Havana are linked with reduced white matter fibre density.

Diplomats representing the USA have reported with unusual neurologic symptoms and MRI changes after being posted in Havana, Cuba between late 2016 and 2018. Here, we examined white matter microstructure and network connectivity of individuals stationed in Havana, using diffusion-weighted MRI, fixel-based analysis and structural connectomics as implemented in MRtrix3. MRI data acquisition and clinical assessments were done in a total of 24 diplomats and their family members and 40 healthy controls. The diplomat data were grouped into an exposed cohort ( = 16) and an unexposed cohort ( = 10), and among these, two individuals were assessed before and after potential exposure. Fixel-based analysis revealed a reduction in fibre density in two specific regions: the fornix and the splenium, in exposed individuals, relative to unexposed individuals and healthy controls. analyses showed the effect remained present ( < 0.05) in both regions when comparing exposed and unexposed diplomats; and reduced fibre density was correlated with longer time period stationed in Cuba after age correction. Reduction of fibre density was also found to be linked with clinical symptoms of persistent migraine, tinnitus, sound sensitivity and fatigue. Network statistical comparisons revealed decreased structural connectivity in two distinct networks, comprising subcortical and cortical systems in exposed individuals, relative to unexposed and normative data. While the cause for the differences between the groups remains unknown, our results reveal region-specific white matter injury, that is, significantly correlated with clinical symptoms.

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Real-world evidence of sustained improvement following 60-day peripheral nerve stimulation treatment for pain: a cross-sectional follow-up survey.

This study presents real-world data from a cross-sectional follow-up survey of patients who previously received 60-day peripheral nerve stimulation (PNS) treatment for pain. A survey including validated pain and other related outcome measures was distributed to patients who previously underwent implantation of temporary PNS leads for 60-day PNS treatment. Among survey respondents who were at least 3 months from the start of treatment, most reported sustained clinically significant improvements in pain and/or quality of life, with the length of follow-up at the time of survey completion ranging from 3 to 30 months. These real-world data support recent prospective studies indicating that 60-day percutaneous PNS provides significant and sustained relief across a wide range of pain conditions.

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A real-world study of acute and preventive medication use, adherence, and persistence in patients prescribed fremanezumab in the United States.

Following approval of fremanezumab for the prevention of migraine in adults, health care decision makers are interested in understanding real-world clinical characteristics and treatment patterns among patients initiating fremanezumab therapy.

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Calcitonin gene-related peptide-targeting drugs and Raynaud’s phenomenon: a real-world potential safety signal from the WHO pharmacovigilance database.

Migraine is responsible for significant disability and societal burden. Recently, drugs targeting the calcitonin gene-related peptide (CGRP) pathway raised new hopes. CGRP, a potent vasodilator, plays a key role in the pathogenesis of migraine attacks. The deficiency of CGRP is involved in Raynaud's phenomenon, which consists of abnormal vasoconstriction of the digits. We aimed to assess the potential association of Raynaud's phenomenon with CGRP-targeting drugs, analyzing real-world data from the World Health Organization (VigiBase®).

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Attenuated G protein signaling and minimal receptor phosphorylation as a biochemical signature of low side-effect opioid analgesics.

Multi-receptor targeting has been proposed as a promising strategy for the development of opioid analgesics with fewer side effects. Cebranopadol and AT-121 are prototypical bifunctional ligands targeting the nociceptin/orphanin FQ peptide receptor (NOP) and µ-opioid receptor (MOP) that elicit potent analgesia in humans and nonhuman primates, respectively. Cebranopadol was reported to produce typical MOP-related side effects such as respiratory depression and reward, whereas AT-121 appeared to be devoid of these liabilities. However, the molecular basis underlying different side effect profiles in opioid analgesics remains unknown. Here, we examine agonist-induced receptor phosphorylation and G protein signaling profiles of a series of chemically diverse mixed MOP/NOP agonists, including cebranopadol and AT-121. We found that these compounds produce strikingly different MOP phosphorylation profiles. Cebranopadol, AT-034 and AT-324 stimulated extensive MOP phosphorylation, whereas AT-201 induced selective phosphorylation at S375 only. AT-121, on the other hand, did not promote any detectable MOP phosphorylation. Conversely, none of these compounds was able to elicit strong NOP phosphorylation and low NOP receptor phosphorylation correlated with partial agonism in a GIRK-channel assay. Our results suggest a close correlation between MOP receptor phosphorylation and side effect profile. Thus, bifunctional MOP/NOP opioid ligands combining low efficacy G protein signaling at both NOP and MOP with no detectable receptor phosphorylation appear to be devoid of side-effects such as respiratory depression, abuse liability or tolerance development, as with AT-121.

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Symptom-based pharmacotherapy for neuropathic pain related to spinal disorders: results from a patient-based assessment.

Existing guidelines advocate an updated therapeutic algorithm for chronic neuropathic pain (NeP), but pharmacotherapeutic management should be individualized to pain phenotypes to achieve higher efficacy. This study was aimed to evaluate the efficacy of medications, based on NeP phenotypes, and to propose symptom-based pharmacotherapy. This retrospective study was enrolled 265 outpatients with chronic NeP related to spinal disorders. The patients were classified into three groups: spinal cord-related pain, radicular pain, and cauda equina syndrome. Data were obtained from patient-based questionnaires using Neuropathic Pain Symptom Inventory (NPSI) and the Brief Scale for Psychiatric Problems in Orthopaedic Patients, and from clinical information. The proportions of patients with ≥ 30% and ≥ 50% reduction in NPSI score for each pain subtype (spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia) and drugs were evaluated. The pain reduction rate was significantly lower in patients with spinal cord-related pain, especially for paresthesia/dysesthesia. For spinal cord-related pain, duloxetine and neurotropin had insufficient analgesic effects, whereas mirogabalin was the most effective. Pregabalin or mirogabalin for radicular pain and duloxetine for cauda equina syndrome are recommended in cases of insufficient analgesic effects with neurotropin. The findings could contribute to better strategies for symptom-based pharmacotherapeutic management.

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Be in it for the long haul: a commentary on human tissue recovery initiatives.

The strong need for a new foundational molecular framework for human nervous system research at the nociceptive level is now matched by comprehensive and quantitative capabilities for analyzing nociceptive tissues such as pathological peripheral tissue, damaged peripheral nerve, dorsal root ganglia, spinal cord, and brain, where possible. However, this idea must be matched by equally strong organization and infrastructures for multisite tissue recovery, molecular analyses, data sharing, and long-term archiving. Experience from other human tissue analysis projects shows that a decades long activity may be expected, hence "Be in it for the long haul." While certain milestones can be met fairly quickly, others aimed at molecular and neuroanatomical characterization of chronic pain disorders will require the sustained attention of the groups involved. This can yield a valuable addition to basic and translational pain research and the development of new treatments whose targets are validated directly in humans. Perspective: A concerted effort is needed to build human nociceptive tissue banks for multi-omic research. In addition to collecting tissue, a careful characterization of pain problems from donors is essential, as is a parallel effort to assess their concurrent medical problems, medications, and the many variables of general human activity and lifestyle that can impact the results. Given the projected long time frame, in addition to maintaining funding, sustaining motivation and momentum are critical factors for success.

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Diagnosis and Management of Lumbar Spinal Stenosis: A Review.

Lumbar spinal stenosis is a prevalent and disabling cause of low back and leg pain in older persons, affecting an estimated 103 million persons worldwide. Most are treated nonoperatively. Approximately 600 000 surgical procedures are performed in the US each year for lumbar spinal stenosis.

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Inequalities and inequities in the types of chronic pain services available in areas of differing deprivation across England.

In England, the prevalence of chronic pain is higher in more deprived compared to less deprived areas. Patients in such areas also experience more severe and disabling pain than those in less deprived areas. However, little is known about whether the distribution of services for chronic pain reflect these ranging levels of need. This study examines how the types of services available for chronic pain patients vary between healthcare providers in England, serving areas of differing deprivation.

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Central and peripheral contributions of T-type calcium channels in pain.

Chronic pain is a severely debilitating condition that reflects a long-term sensitization of signal transduction in the afferent pain pathway. Among the key players in this pathway are T-type calcium channels, in particular the Ca3.2 isoform. Because of their biophysical characteristics, these channels are ideally suited towards regulating neuronal excitability. Recent evidence suggests that T-type channels contribute to excitability of neurons all along the ascending and descending pain pathways, within primary afferent neurons, spinal dorsal horn neurons, and within pain-processing neurons in the midbrain and cortex. Here we review the contribution of T-type channels to neuronal excitability and function in each of these neuronal populations and how they are dysregulated in chronic pain conditions. Finally, we discuss their molecular pharmacology and the potential role of these channels as therapeutic targets for chronic pain.

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Role of cathepsin K in the expression of mechanical hypersensitivity following intra-plantar inflammation.

Persistent/chronic inflammatory pain involves multiple pathophysiological mechanisms and is far more complex than acute/momentary pain. Current therapeutics for chronic inflammatory pain are often not effective because the etiology responsible for the pain is not addressed by traditional pharmacological treatments. Cathepsin K is a cysteine protease that has mostly been studied in the context of bone and joint disorders. Previous work by others has shown that inhibition of cathepsin K activity reduces osteoarthritis-associated nociception in joints. However, the role of cathepsin K in cutaneous inflammation is understudied. We assessed the effectiveness of genetic deletion or pharmacological inhibition of cathepsin K in male mice on the expression of nocifensive behaviors after formalin injection or mechanical and thermal hypersensitivity after injection of complete Freund's adjuvant (CFA) into the mouse hind paw. Our data demonstrate that cathepsin K knockout mice (Ctsk) have a reduction in nocifensive behaviors in the formalin test. In addition, Ctsk do not develop mechanical hypersensitivity after CFA injection for up to 7 days. Moreover, we found that inhibition of cathepsin K reduced mechanical hypersensitivity after CFA injection and mRNA levels, protein levels, and cathepsin K activity levels were elevated after CFA injection. Based upon our data, cathepsin K is indicated to play a role in the expression of chemically-induced cutaneous hypersensitivity, as Ctsk mice do not develop mechanical hypersensitivity and show a reduction in nocifensive behaviors. Further research is needed to determine whether attenuating cathepsin K activity may generate a clinically relevant therapeutic.

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Cannabinoid CB2 receptors are upregulated via bivalent histone modifications and control primary afferent input to the spinal cord in neuropathic pain.

Type-2 cannabinoid receptors (CB2, encoded by the Cnr2 gene) are mainly expressed in immune cells, and CB2 agonists normally have no analgesic effect. However, nerve injury upregulates CB2 in the dorsal root ganglion (DRG), following which CB2 stimulation reduces neuropathic pain. It is unclear how nerve injury increases CB2 expression or how CB2 activity is transformed in neuropathic pain. In this study, immunoblotting showed that spinal nerve ligation (SNL) induced a delayed and sustained increase in CB2 expression in the DRG and dorsal spinal cord synaptosomes. RNAscope in situ hybridization also showed that SNL substantially increased CB2 mRNA levels, mostly in medium and large DRG neurons. Furthermore, we found that the specific CB2 agonist JWH-133 significantly inhibits the amplitude of dorsal root-evoked glutamatergic excitatory postsynaptic currents in spinal dorsal horn neurons in SNL rats, but not in sham control rats; intrathecal injection of JWH-133 reversed pain hypersensitivity in SNL rats, but had no effect in sham control rats. In addition, chromatin immunoprecipitation-qPCR analysis showed that SNL increased enrichment of two activating histone marks (H3K4me3 and H3K9ac) and diminished occupancy of two repressive histone marks (H3K9me2 and H3K27me3) at the Cnr2 promoter in the DRG. In contrast, SNL had no effect on DNA methylation levels around the Cnr2 promoter. Our findings suggest that peripheral nerve injury promotes CB2 expression in primary sensory neurons via epigenetic bivalent histone modifications and that CB2 activation reduces neuropathic pain by attenuating nociceptive transmission from primary afferent nerves to the spinal cord.

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The Last Decade Publications on Diabetic Peripheral Neuropathic Pain: A Bibliometric Analysis.

Diabetic peripheral neuropathic pain (DPNP) is a usual complication of diabetes with a high incidence and mortality. Many diabetes-related studies have been published in various journals. However, bibliometrics and visual analyses in the domain of DPNP research are still lacking. The study aimed to offer a visual method to observe the systematic overview of global research in this field from 2011 to 2021.

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Bradykinin-Induced Sensitization of Transient Receptor Potential Channel Melastatin 3 Calcium Responses in Mouse Nociceptive Neurons.

TRPM3 is a calcium-permeable cation channel expressed in a range of sensory neurons that can be activated by heat and the endogenous steroid pregnenolone sulfate (PS). During inflammation, the expression and function of TRPM3 are both augmented in somatosensory nociceptors. However, in isolated dorsal root ganglion (DRG) neurons application of inflammatory mediators like prostaglandins and bradykinin (BK) inhibit TRPM3. Therefore, the aim of this study was to examine the effect of preceding activation of cultured 1 day old mouse DRG neurons by the inflammatory mediator BK on TRPM3-mediated calcium responses. Calcium signals were recorded using the intensity-based dye Fluo-8. We found that TRPM3-mediated calcium responses to PS were enhanced by preceding application of BK in cells that responded to BK with a calcium signal, indicating BK receptor (BKR) expression. The majority of cells that co-expressed TRPM3 and BKRs also expressed TRPV1, however, only a small fraction co-expressed TRPA1, identified by calcium responses to capsaicin and supercinnamaldehyde, respectively. Signaling and trafficking pathways responsible for sensitization of TRPM3 following BK were characterized using inhibitors of second messenger signaling cascades and exocytosis. Pharmacological blockade of protein kinase C, calcium-calmodulin-dependent protein kinase II and diacylglycerol (DAG) lipase did not affect BK-induced sensitization, but inhibition of DAG kinase did. In addition, release of calcium from intracellular stores using thapsigargin also resulted in TRPM3 sensitization. Finally, BK did not sensitize TRPM3 in the presence of exocytosis inhibitors. Collectively, we show that preceding activation of DRG neurons by BK sensitized TRPM3-mediated calcium responses to PS. Our results indicate that BKR-mediated activation of intracellular signaling pathways comprising DAG kinase, calcium and exocytosis may contribute to TRPM3 sensitization during inflammation.

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Sex-Specific B Cell and Anti-Myelin Autoantibody Response After Peripheral Nerve Injury.

Immunotherapy holds promise as a non-addictive treatment of refractory chronic pain states. Increasingly, sex is recognized to impact immune regulation of pain states, including mechanical allodynia (pain from non-painful stimulation) that follows peripheral nerve trauma. This study aims to assess the role of B cells in sex-specific responses to peripheral nerve trauma. Using a rat model of sciatic nerve chronic constriction injury (CCI), we analyzed sex differences in (i) the release of the immunodominant neural epitopes of myelin basic protein (MBP); (ii) the levels of serum immunoglobulin M (IgM)/immunoglobulin G (IgG) autoantibodies against the MBP epitopes; (iii) endoneurial B cell/CD20 levels; and (iv) mechanical sensitivity behavior after B cell/CD20 targeting with intravenous (IV) Rituximab (RTX) and control, IV immunoglobulin (IVIG), therapy. The persistent MBP epitope release in CCI nerves of both sexes was accompanied by the serum anti-MBP IgM autoantibody in female CCI rats alone. IV RTX therapy during CD20-reactive cell infiltration of nerves of both sexes reduced mechanical allodynia in females but not in males. IVIG and vehicle treatments had no effect in either sex. These findings provide strong evidence for sexual dimorphism in B-cell function after peripheral nervous system (PNS) trauma and autoimmune pathogenesis of neuropathic pain, potentially amenable to immunotherapeutic intervention, particularly in females. A myelin-targeted serum autoantibody may serve as a biomarker of such painful states. This insight into the biological basis of sex-specific response to neuraxial injury will help personalize regenerative and analgesic therapies.

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Protein Tyrosine Phosphatase Receptor Type D Regulates Neuropathic Pain After Nerve Injury the STING-IFN-I Pathway.

Neuropathic pain is usually caused by injury or dysfunction of the somatosensory system, and medicine is a common way of treatment. Currently, there are still no satisfactory drugs, like opioids and lidocaine, which carry a high risk of addiction. Protein tyrosine phosphatase receptor type D (PTPRD) is a known therapeutic target in addiction pathways and small molecule inhibitors targeting it, such as 7-butoxy illudalic acid analog (7-BIA), have recently been developed to tackle addition. PTPRD is also upregulated in the dorsal root ganglion (DRG) in a rat model of neuropathic pain, but is not yet clear whether PTPRD contributes to the development of neuropathic pain. Here, we established a chronic constriction injury (CCI) and evaluated PTPRD expression and its association with neuropathic pain. PTPRD expression was found to gradually increase after CCI in DRGs, and its expression was concomitant with the progressive development of hypersensitivity as assessed by both mechanical and thermal stimuli. Both PTPRD knockdown and administration of PTPRD inhibitor 7-BIA alleviated CCI-induced neuropathic pain while upregulating STING and IFN-α in the DRG. Treatment with H-151, a STING inhibitor, abolished the analgesic effects of PTPRD knockdown. Taken together, our study suggests that increased levels of PTPRD in the DRG following CCI are involved in the development of neuropathic pain the STING-IFN-I pathway. 7-BIA, a small molecule inhibitor of PTPRD with anti-addiction effects, may represent a novel and safe therapeutic strategy for the clinical management of neuropathic pain without the risk of addiction.

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Glutamatergic Neurons in the Amygdala Are Involved in Paclitaxel-Induced Pain and Anxiety.

Paclitaxel is widely used as a first-line chemotherapy agent to treat malignant tumors. However, paclitaxel causes peripheral nerve fiber damage and neuropathic pain in some patients. In addition, patients received paclitaxel chemotherapy are often accompanied by negative emotions such as anxiety. The amygdala is critically involved in regulating pain signals, as well as anxiety. The purpose of this study is to clarify the role of Ca/calmodulin-dependent protein kinase II (CaMKII)-positive glutamatergic neurons in the amygdala in paclitaxel-induced pain and negative affective symptoms. Intraperitoneal injection of paclitaxel into mice caused mechanical and thermal allodynia, as measured by Von Frey test and Hargreaves test, and anxiety, as measured by open field test and elevated plus maze test. Immunofluorescence staining revealed that c-fos-positive neurons were significantly more in the basolateral amygdala (BLA) and central amygdala (CeA) in paclitaxel-treated mice than untreated mice. Furthermore, part of c-fos-positive neurons in the BLA were immunoreactive of CaMKII. Engineered Designer receptors exclusively activated by designer drugs (DREADD) receptor hM4Di or hM3Dq was selectively expressed on CaMKII neurons by injection of adeno-associated virus (AAV) vectors containing CaMKII and hM4Di or hM3Dq. Administration of DREADD agonist CNO to selectively inhibit the CaMKII neurons in the BLA significantly increased the paw withdrawal thresholds and paw withdrawal latencies. In addition, selectively inhibition of CaMKII neurons in the BLA alleviated anxiety behavior without affecting the motor activity. In summary, our findings suggest that CaMKII neurons in the amygdala are critical for neuropathic pain and anxiety behaviors induced by paclitaxel chemotherapy.

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Development and validation of a web-based headache diagnosis questionnaire.

Information technology advances may help in conducting epidemiological studies using web-based surveys. Questionnaire-based headache diagnosis should be validated against the doctor's diagnosis. This study aimed to develop and validate a web-based diagnostic questionnaire for migraine, probable migraine (PM), and tension-type headache (TTH). We constructed a seven-item questionnaire for diagnosing migraine, PM, and TTH. A web-based survey was conducted among adults aged 20-59 years; migraine, PM, and TTH were diagnosed based on the responses. Validation interview was performed via telephone by a neurologist within 1 month after the web-based interview. Finally, 256 participants completed both web-based survey and validation interview. Of them, 121 (47.3%), 65 (25.4%), 61 (23.8%), and 9 (3.5%) were diagnosed with migraine, PM, TTH, and unclassified headache (UH), respectively in the web-based survey, whereas 119 (46.5%), 60 (23.4%), 74 (28.9%), 2 (0.8%), and 1 (0.4%) were diagnosed with migraine, PM, TTH, UH, and primary stabbing headache, respectively in the validation interview. The best agreement was found in migraine (sensitivity: 92.6%; specificity: 94.8%; kappa coefficient: 0.875), followed by TTH (sensitivity: 78.4%; specificity: 98.4%; kappa coefficient: 0.809). PM showed the least agreement (sensitivity: 85.0%; specificity: 92.9%; kappa coefficient: 0.757). In conclusion, our questionnaire is valid in identifying these headache disorders.

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Complex pain phenotypes: Suicidal ideation and attempt through latent multimorbidity.

Given the relatively high rates of suicidal ideation and attempt among people with chronic pain, there is a need to understand the underlying factors to target suicide prevention efforts. To date, no study has examined the association between pain phenotypes and suicide related behaviors among those with mild traumatic brain injuries.

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Design and development of novel, short, stable dynorphin-based opioid agonists for safer analgesic therapy.

The kappa opioid receptor has exceptional potential as an analgesic target, seemingly devoid of the many peripheral side-effects of Mu opioid receptors. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally-mediated side effects have limited their clinical translation. Here, we modify an active endogenous dynorphin peptide to improve drug-likeness and develop safer KOPr agonists for clinical use.

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IL-20 promotes cutaneous inflammation and peripheral itch sensation in atopic dermatitis.

Atopic dermatitis (AD) is a chronic skin disease, which is associated with intense itch, skin barrier dysfunction and eczematous lesions. Aberrant IL-20 expression has been implicated in numerous inflammatory diseases, including psoriasis. However, the role of IL-20 in AD remains unknown. Here, RNA-seq, Q-PCR, and immunocytochemistry were utilized to examine disease-driven changes of IL-20 and its cognate receptor subunits in skin from healthy human subjects, AD patients and murine AD-models. Calcium imaging, knockdown and cytokine array were used to investigate IL-20-evoked responses in keratinocytes and sensory neurons. The murine cheek model and behavioral scoring were employed to evaluate IL-20-elicited sensations in vivo. We found that transcripts and protein of IL-20 were upregulated in skin from human AD and murine AD-like models. Topical MC903 treatment in mice ear enhanced IL-20R1 expression in the trigeminal sensory ganglia, suggesting a lesion-associated and epidermal-driven mechanism for sensitization of sensory IL-20 signaling. IL-20 triggered calcium influx in both keratinocytes and sensory neurons, and promoted their AD-related molecule release and transcription of itch-related genes. In sensory neurons, IL-20 application increased TLR2 transcripts, implicating a link between innate immune response and IL-20. In a murine cheek model of acute itch, intradermal injection IL-20 and IL-13 elicited significant itch-like behavior, though only when co-injected. Our findings provide novel insights into IL-20 function in peripheral (skin-derived) itch and clinically relevant intercellular neuron-epidermal communication, highlighting a role of IL-20 signaling in the pathophysiology of AD, thus forming a new basis for the development of a novel antipruritic strategy via interrupting IL-20 epidermal pathways.

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Central effects of galcanezumab in migraine: a pilot study on Steady State Visual Evoked Potentials and occipital hemodynamic response in migraine patients.

The discovery of the prominent action of Calcitonin Gene Related Peptide -CGRP- on trigeminal afferents and meningeal vessels, opened a new era in migraine treatment. However, how the block of nociceptive afferents could act on central mechanisms of migraine is still not clear. In this pilot study we aimed to test the effect of 3 months Galcanezumab (CGA) therapy on occipital visual reactivity in migraine patients, using the Steady State Visual Evoked Potentials-SSVEPs and Functional Near Infrared Spectroscopy -fNIRS.

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Interictal plasma glutamate levels are elevated in individuals with episodic and chronic migraine.

Glutamate is implicated in migraine pathogenesis including central sensitization and pain transmission. Altered plasma glutamate levels has been noted in migraine. Chronic migraine (CM) presented a higher degree of central sensitization and pain transmission than episodic migraine (EM). However, no study has evaluated plasma glutamate levels separately in EM and CM. This study aimed to assess plasma glutamate levels in EM and CM compared to controls. An enzyme-linked immunosorbent assay was used to assess plasma glutamate levels in females with EM (n = 98) and CM (n = 92) as well as controls (n = 50). Plasma glutamate levels in participants with EM (median and interquartile range, 49.73 [40.82-66.12] μmol/L, p < 0.001) and CM (58.70 [44.64-72.46] μmol/L, p < 0.001) were significantly higher than those in controls (38.79 [29.50-53.60] μmol/L). Glutamate levels were not significantly different between participants with EM and CM (p = 0.075). There was no significant association of plasma glutamate levels with headache frequency (exponential and 95% confidence interval, 1.285 [0.941-1.755]) and intensity (mild, 59.95 [59.95-59.95] μmol/L vs. moderate, 52.76 [40.83-106.89] μmol/L vs. severe, 55.16 [42.34-68.03] μmol/L, p = 0.472). The plasma glutamate level is a potential indicator for EM and CM.

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Mechanism of dexmedetomidine preconditioning on spinal cord analgesia in rats with functional chronic visceral pain.

To analyze the effect and mechanism of dexmedetomidine (DEX) analgesia pretreatment on functional chronic visceral pain in rats.

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Virtual Reality-Based Mindfulness for Chronic Pain Management: A Scoping Review.

To identify and synthesize the scientific literature on virtual reality (VR)-based mindfulness applications for the management of chronic pain in adults.

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The Relationship Between Financial Stressors, Chronic Pain, and High-Impact Chronic Pain: Findings From the 2019 National Health Interview Survey.

Public health interventions to prevent financial stressors and reduce chronic pain and high-impact chronic pain (HICP) are important to potentially improve the health of the US population. The objectives of our study were to provide an update on the prevalence of chronic pain and HICP and to examine relationships between financial stressors and pain.

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Pharmacokinetics, safety and efficacy of intra-articular non-steroidal anti-inflammatory drug injections for the treatment of osteoarthritis: A narrative review.

Osteoarthritis (OA) is a common cause of joint disease and activity limitation in adults. Common therapies to treat OA-related pain are oral and topical non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular (IA) corticosteroids. However, prolonged courses of oral NSAIDs are associated with systemic adverse effects and repeat IA corticosteroid injections may cause cartilage degeneration. IA NSAIDs may be an alternative therapy possibly minimizing systemic side effects while maintaining efficacy. Therefore, we sought to summarize the pharmacokinetics, safety and efficacy of IA NSAIDs to help providers make a more informed decision on the use of IA NSAIDs.

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Psychological stress in rheumatoid arthritis: a systematic scoping review.

Rheumatoid arthritis (RA) considerably impacts patients' mental health. However, it is largely unclear how people suffering from RA experience psychological stress beyond depression or anxiety, and what drives stress in these patients.

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Risk factors of white matter hyperintensities in migraine patients.

Migraine frequently is associated with White Matter Hyperintensities (WMHs). We aimed to assess the frequency of WMHs in migraine and to assess their risk factors.

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NICE chronic primary pain guidelines: what the busy GP needs to know.

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Stigma by Association: To what Extent is the Attitude Toward Naloxone Affected by the Stigma of Opioid Use Disorder?

The United States opioid epidemic is fueled by illicit opioid abuse and prescription opioid misuse and abuse. Consequently, cases of opioid use disorder (OUD, opioid addiction), opioid overdose, and related deaths have increased since the year 2000. Naloxone is an opioid antagonist that rapidly reverses opioid intoxication to prevent death from overdose. It is one of the major risk mitigation strategies recommended in the 2016 Centers for Disease Control and Prevention Guideline for Prescribing Opioids for Chronic Pain. However, despite the exponential increase in dispensing and distribution of naloxone, opioid overdose and related deaths have continued to increase; suggesting that the increased naloxone supply still lags the need. This discordance is attributed at least in part to the negative attitude toward naloxone, which is based on the belief that naloxone is only meant for "addicts" and "abusers" (OUD patients). This negative attitude or so-called naloxone stigma is therefore considered a major barrier for naloxone distribution and consequently, overdose-death prevention efforts. This article presents evidence that challenges common assertions about OUD stigma being the sole and direct driving force behind naloxone stigma, and the purported magnitude of the barrier that naloxone stigma constitutes for naloxone distribution programs among the stakeholders (patients, pharmacists, and prescribers). The case was then made to operationalize and quantify the construct among the stakeholders to determine the extent to which OUD stigma drives naloxone stigma, and the relative impact of naloxone stigma as a barrier for naloxone distribution efforts.

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Optimization of 4-arylthiophene-3-carboxylic acid derivatives as inhibitors of ANO1: Lead optimization studies toward their analgesic efficacy for inflammatory pain.

Current pain management is largely limited to opioids and non-steroidal anti-inflammatory drugs. Developing new analgesic drugs remains important to address the unmet medical needs of chronic pain patients. Calcium-activated chloride channel anoctamin-1 (ANO1) is a potential analgesic target. ANO1 is activated by noxious stimuli in peripheral sensory neurons and further induced neural depolarization. Downregulation of ANO1 reduced hyperalgesia and allodynia caused by inflammation and nerve injury. Here we developed a series of 4-arylthiophene-3-carboxylic acid derivatives for proof-of-concept studies of ANO1-targeted analgesia. These efforts led to the identification of the compound DFBTA, 4-(4-chlorophenyl)-2-(2,5-difluorobenzamido)thiophene-3-carboxylic acid, which displays dramatic ANO1 inhibition with IC of 24 nM. DFBTA displays very weak cytotoxicity, cardiotoxicity, and acute toxicity (HEK293 proliferation IC > 30 μM, hERG IC > 30 μM, mouse minimum lethal dosage, MLD>1000 mg/kg), as well as excellent pharmacokinetics properties with oral bioavailability >75% and little brain penetration (<1.5% brain/plasma). Finally, the analgesic efficacy of ANO1 inhibitor was evaluated in animal models. DFBTA shown comparable efficacy to clinical drugs in all inflammatory pain models induced by complete Freund's adjuvant, formalin, and capsaicin. These works provide a useful tool compound and promising results for ANO1-targenting analgesic development.

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A Bibliometric of Trends on Acupuncture Research About Migraine: Quantitative and Qualitative Analyses.

Migraine is a common neurovascular disorder disease often characterized by episodic headaches that can develop chronic disorders. Acupuncture as a non-pharmacological therapy has been extensively used to manage migraine prevention and treatment in clinical practice. Many studies focused on acupuncture therapy for migraine, but none analyzed the publications quantitatively and qualitatively. The aim of this study is to show the recent researches and trend of advances in this field based on quantitative and qualitative analyses.

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A Novel Spinal Cord Stimulation System with a Battery-Free Micro Implantable Pulse Generator.

Spinal cord stimulation (SCS) is effective for the treatment of chronic intractable pain of the trunk and limbs. The mechanism of action may be based, at least in part, upon the gate control theory; however, new waveforms may suggest other mechanisms. Although benefits of the SCS technology generally outweigh the complications associated with SCS, some complications such as infection and skin erosion over the implant can result in device removal. Additional reasons for device removal, such as pocket pain and battery depletion, have driven technological innovations including battery-free implants and device miniaturization. The neurostimulation system described here was specifically designed to address complications commonly associated with implantable batteries and/or larger implantable devices. The benefits of the small size are further augmented by a minimally invasive implant procedure. Usability data show that patients found this novel neurostimulation system to be easy to use and comfortable to wear. What is more, clinical data demonstrate that the use of this system provides statistically significant reduction in pain scores with responder rates (defined as ≥ 50% reduction in pain) of 78% in the low back and 83% in the leg(s). Advances in miniaturization technology arose from the considerable shrinkage of the integrated circuit, with an increase in performance, according to Moore's law (1965). However, commensurate improvements in battery technology have not maintained a similar pace. This has prompted some manufacturers to place the battery outside, against the skin, thereby allowing a massive reduction in the implant volume, with the hopes of fewer device-related complications.

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Migraine and adverse pregnancy outcomes: the nuMoM2b study.

Migraine affects 28% of women in their pregnancy-capable years, and is associated with systemic inflammation, endothelial dysfunction, and increased risk of pregnancy-associated thromboembolic events. Migraine history has been associated with adverse pregnancy outcomes (APO) of placental origin, including hypertensive disorders of pregnancy (HDP) and preterm birth (PTB). We tested the hypothesis that self-reported migraine in nulliparous individuals is associated with higher odds of APO.

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Assessing central sensitization with quantitative sensory testing in inflammatory rheumatic diseases: a systematic review.

The major therapeutic challenge in inflammatory rheumatic diseases is the persistence of pain despite good responses to specific therapies. Central sensitization, which can be assessed clinically by psychophysical measurements, including quantitative sensory testing (QST), is a widely proposed mechanism for chronic pain. In this systematic review, we explored the scientific literature addressing quantitative sensory testing in inflammatory rheumatic diseases. We searched Pubmed and Embase for publications up to December 2021 concerning studies on quantitative sensory testing focusing on pain thresholds, temporal summation (TS) and conditioned pain modulation (CPM), in adult patients with chronic inflammatory rheumatism (e.g. rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis). The exclusion criteria were reviews, inclusion of children and no reported pain threshold. Data quality was assessed with the National Institutes of Health (NIH) Quality Assessment tools. We identified 27 studies (18 controlled, 9 uncontrolled) including 1875 patients with inflammatory rheumatic diseases and 795 controls. A decrease in pressure pain threshold, in favor of allodynia, was found in 12 of 14 controlled studies on patients with rheumatoid arthritis and spondyloarthritis. The results of other psychophysical tests, including TS and CPM, were inconsistent due to population heterogeneity and a lack of standardization of the patients' disease duration, activity and treatment. Our review shows that pain in chronic inflammatory rheumatism is associated with pressure allodynia. However, given the heterogeneous quality and discrepant results of studies of other QST outcome measures, the hypothesis of central sensitization involvement in pain processing in these patients cannot be confirmed.

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Cannabidiol (CBD) in Rheumatic Diseases (Musculoskeletal Pain).

This review will address the many uncertainties surrounding the medical use of cannabidiol (CBD). We will begin with an overview of the legal and commercial environment, examine recent preclinical and clinical evidence on CBD, explore questions concerning CBD raised by healthcare professionals and patients, investigate dosing regimens and methods of administration, and address current challenges in the accumulation of sound evidence.

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Baricitinib: A Review in Moderate to Severe Atopic Dermatitis.

Baricitinib (Olumiant) is an oral small molecule inhibitor of Janus kinase (JAK)1 and JAK2, which have been implicated in the pathogenesis of atopic dermatitis (AD). In phase III studies in adults with moderate to severe AD who were inadequately controlled with topical corticosteroids (TCS) or systemic treatments (e.g. ciclosporin), or for whom these therapies were not advisable, baricitinib, alone or in combination with TCS, achieved significant and/or clinically relevant improvements in multiple measures of disease severity, pruritus, skin pain, sleep disturbance and health-related quality of life (HR-QOL) over 16 weeks. Benefit onset was rapid, with efficacy generally sustained over the longer term (treatment duration ≤ 68 weeks). In this patient population, the safety profile of baricitinib was consistent with that established in the moderate to severe rheumatoid arthritis (RA) population. Although further longer-term data would be beneficial, current evidence indicates that baricitinib, alone or in combination with TCS, provides an oral alternative to subcutaneous biologics for the treatment of moderate to severe AD in adults who are candidates for systemic therapy.

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Cannabinoids and Pain for the Plastic Surgeon: What Is the Evidence?

Since the passage of the 2018 Farm Bill, practitioners have encountered more patients self-treating pain with over-the-counter topical cannabidiol (CBD) derived from hemp-Cannabis sativa with less than 0.3% delta-9-tetrahydrocannabinol-with reported improvements in pain control and activities of daily living. Cannabidiol has been touted for its capacity to improve inflammatory, arthritic, and neuropathic pain conditions, and increasing numbers of patients are exploring its use as potential replacement for opioids. However, limited rigorous clinical trials have been performed evaluating the safety and efficacy of cannabinoids for the treatment of pain.

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Treatment of migraine with monoclonal antibodies.

: In the few last years, a new family of drugs, anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs), has been developed for migraine therapy. Anti-CGRP mAbs are highly effective, but the current limited experience with their use and their high-cost warrant establishing certain rules of use.

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Immunotargets and Therapy for Prurigo Nodularis.

Prurigo nodularis is a chronic inflammatory skin disease consisting of severely pruritic nodules that can be very debilitating for patients. The basis of this skin condition is immunological dysregulation and neural amplification, driven by T-lymphocytes, mast cells, eosinophilic granulocytes, macrophages, and cytokines mediating itchy processes. Further complicating this already taxing diagnosis is the lack of approved treatment and consensus on management; although there are off-label treatments utilized as therapy. Immunomodulators are the cornerstone of treatment for PN, and additional novel therapies targeting key players in the immunological cascade are currently undergoing investigation. In this review, we will highlight targets of the immune cascade and explore current immunomodulating treatments as well as immunotherapies on the horizon for the management of prurigo nodularis.

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Neuroplasticity related to chronic pain and its modulation by microglia.

Neuropathic pain is often chronic and can persist after overt tissue damage heals, suggesting that its underlying mechanism involves the alteration of neuronal function. Such an alteration can be a direct consequence of nerve damage or a result of neuroplasticity secondary to the damage to tissues or to neurons. Recent studies have shown that neuroplasticity is linked to causing neuropathic pain in response to nerve damage, which may occur adjacent to or remotely from the site of injury. Furthermore, studies have revealed that neuroplasticity relevant to chronic pain is modulated by microglia, resident immune cells of the central nervous system (CNS). Microglia may directly contribute to synaptic remodeling and altering pain circuits, or indirectly contribute to neuroplasticity through property changes, including the secretion of growth factors. We herein highlight the mechanisms underlying neuroplasticity that occur in the somatosensory circuit of the spinal dorsal horn, thalamus, and cortex associated with chronic pain following injury to the peripheral nervous system (PNS) or CNS. We also discuss the dynamic functions of microglia in shaping neuroplasticity related to chronic pain. We suggest further understanding of post-injury ectopic plasticity in the somatosensory circuits may shed light on the differential mechanisms underlying nociceptive, neuropathic, and nociplastic-type pain. While one of the prominent roles played by microglia appears to be the modulation of post-injury neuroplasticity. Therefore, future molecular- or genetics-based studies that address microglia-mediated post-injury neuroplasticity may contribute to the development of novel therapies for chronic pain.

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Comparison of the serum brain-derived neurotrophic factor (BDNF) between fibromyalgia and nociceptive pain groups; and effect of duloxetine on the BDNF level.

The primary objective was to compare the serum brain-derived neurotrophic factor (BDNF) level in the patients with two types of pain: fibromyalgia (FM) and non-FM nociceptive pain (non-FM NP). The secondary objective was to investigate the effect of duloxetine on serum BDNF in FM patients and assess the direction of BDNF changes' relation to clinical parameters' alterations.

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Methotrexate promotes recovery of arthritis-induced alveolar bone loss and modifies the composition of the oral-gut microbiota.

The impact of rheumatoid arthritis (RA) on the shaping of the oral and gut microbiome raises the question of whether and how RA treatment modifies microbial communities. We examined changes in the oral and gut microbiota in a mouse model of antigen-induced arthritis (AIA) treated or not with methotrexate (MTX).

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The challenges of treating osteoarthritis pain and opportunities for novel peripherally directed therapeutic strategies.

Osteoarthritis (OA) is a chronic joint disease that represents an increasingly substantial global burden. Joint pain is the most significant symptom of OA. Unfortunately, current pharmacological treatments for OA pain are often not wholly efficacious, or are associated with serious adverse effects. This lack of effective pain relief has seen the prescription of opioids for OA pain increase over the past decades. The long-term adverse effects of prescribed opioids alongside the increasing prevalence of OA pain highlights the need for alternative analgesics. Understanding the mechanisms that drive this chronic joint pain is crucial for the development of novel analgesics. OA is a heterogeneous disease, and this is reflected by the diversity of pain phenotypes in people with the disease. Herein, we review current understanding of the biological changes at the joint and within the central nervous system that drive this chronic pain. We particularly focus on the most recent advances in our understanding of the peripheral nociceptive mechanisms that underlie chronic OA pain and highlight how targeting peripheral OA inflammation may open up opportunities for novel analgesics.

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Multi-data analysis based on an artificial neural network model for long term pain outcome and key predictors of microvascular decompression in trigeminal neuralgia.

To investigate the use of multi-data analysis based on an artificial neural network (ANN) to predict long-term pain outcomes after microvascular decompression (MVD) in patients with trigeminal neuralgia (TN), and to explore key predictors.

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Sleep restriction alters cortical inhibition in migraine: A transcranial magnetic stimulation study.

Migraine is a primary headache disorder with a well-known association with insufficient sleep. However, both the underlying pathophysiology of the disease and the relationship with sleep is still unexplained. In this study, we apply transcranial magnetic stimulation to investigate possible mechanisms of insufficient sleep in migraine.

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Impact of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) on the quality of life of people with ME/CFS and their partners and family members: an online cross-sectional survey.

The aim of this study was to assess the impact of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) on the quality of life (QoL) of people with ME/CFS and their relative or partner (family member).

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Modulation of the kappa and mu opioid axis for the treatment of chronic pruritus: A review of basic science and clinical implications.

Treating chronic pruritus is challenging for dermatologists due to the lack of therapeutic options. We review the effects of κ-opioid receptor (KOR) and μ-opioid receptor (MOR) in the modulation of itch, summarize evidence supporting the efficacy and safety of opioid receptor-targeting agents in chronic pruritus, and address clinical considerations.

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Thermosensitive injectable graphene oxide/chitosan-based nanocomposite hydrogels for controlling the in vivo release of bupivacaine hydrochloride.

Local anesthetics are commonly used for the management of intraoperative and postoperative acute and chronic pain caused by small invasive procedures. However, their short half-life and duration of action limit their clinical benefits. In this study, we proposed the incorporation of graphene oxide (GO) nanosheets to chitosan (CS)/β-glycerophosphate (GP) thermosensitive hydrogel system to form an injectable nanocomposite hydrogel (NCH) with improved mechanical properties and better control over the release of bupivacaine hydrochloride (BH). The prepared nanocomposite hydrogels were characterized for their gelation time, porosity, swelling ratio, injectability, mechanical strength and in vitro drug release. In vivo, the efficacy of the prepared NCH containing 0.5 % w/v BH was evaluated using a thermal nociceptive assay in a rat model. The incorporation of GO significantly enhanced the physicochemical and mechanical properties of the hydrogel scaffolds in a concentration-dependent manner. Inclusion of 0.1% w/v GO resulted in 84% reduction in gelation time and 16% and 40% decrease in the porosity and swelling ratio of the nanocomposite hydrogels, respectively. The mechanical strength of the CS/GP hydrogel scaffolds was also significantly improved in presence of GO. BH was slowly released from the NCHs containing 0.1% w/v GO and resulted in a 55% and 86.43% drug release after 6 and 24 h, respectively. In vivo studies showed that BH-loaded NCH significantly prolonged the local anesthetic effect and resulted in a 6.5-fold increase in blocking the pain sensory reflex compared to BH solution. These results indicate that the incorporation of GO significantly improved the physical and mechanical properties of CS/GP thermosensitive hydrogels and successfully sustained the effect of local anesthesia for more effective pain management.

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New Advances on Pathophysiology of Diabetes Neuropathy and Pain Management: Potential Role of Melatonin and DPP-4 Inhibitors.

Pre-diabetes and diabetes are growing threats to the modern world. Diabetes mellitus (DM) is associated with comorbidities such as hypertension (83.40%), obesity (90.49%), and dyslipidemia (93.43%), creating a substantial burden on patients and society. Reductive and oxidative (Redox) stress level imbalance and inflammation play an important role in DM progression. Various therapeutics have been investigated to treat these neuronal complications. Melatonin and dipeptidyl peptidase IV inhibitors (DPP-4i) are known to possess powerful antioxidant and anti-inflammatory properties and have garnered significant attention in the recent years. In this present review article, we have reviewed the recently published reports on the therapeutic efficiency of melatonin and DPP-4i in the treatment of DM. We summarized the efficacy of melatonin and DPP-4i in DM and associated complications of diabetic neuropathy (DNP) and neuropathic pain. Furthermore, we discussed the mechanisms of action and their efficacy in the alleviation of oxidative stress in DM.

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Postoperative Multimodal Pain Management and Opioid Consumption in Arthroscopy Clinical Trials: A Systematic Review.

To provide an updated review of multimodal pain management in arthroscopic surgery by evaluating pain and opioid consumption after shoulder, knee, and hip arthroscopy.

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Role of Atogepant in the Treatment of Episodic Migraines: Clinical Perspectives and Considerations.

Advances in molecular biology and neuroscience have led to the discovery of calcitonin gene-related peptide (CGRP), a 37 amino-acid neuropeptide that plays a critical role in the pathogenesis of migraine. CGRP receptor antagonist, also known as gepant, is an oral medication that inhibits the CGRP-related nociceptive signaling pathway. To date, three gepants are approved by the FDA for migraine treatment. Atogepant is a 2nd-generation gepant that non-competitively antagonizes CGRP receptors inhibiting neurogenic inflammation and pain sensitization. With its long half-life and minimal cardiovascular or liver toxicity, it is the first in its class approved primarily for migraine prevention. This article will discuss the evidence, safety, and rationale of atogepant for use in clinical practice.

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Salvianolic acid B alleviates comorbid pain in depression induced by chronic restraint stress through inhibiting GABAergic neuron excitation via an ERK-CREB-BDNF axis-dependent mechanism.

Pain comorbid with depression occurred frequently in clinical settings. This study aims to explore the molecular mechanism underlying antidepressant and analgetic effect of salvianolic acid B (SalB) in comorbid pain in depression induced by chronic restraint stress (CRS), which associates with GABAergic neuron activation in the amygdala and the ERK-CREB-BDNF signaling pathway. The differentially expressed genes related to comorbid pain in CRS-induced depression were screened through bioinformatics analysis. After CRS treatment for 3 weeks, depression-like behaviors were developed in GAD2-tdT mice. The retrograde tracer cholera toxin B subunit combined with retrograde tracer CTB-488 was injected into the parafascicular nucleus of thalamus to project GABAergic neurons to observe the labeling of neurons in the whole brain. After treatment with SalB and ERK-CREB-BDNF signaling pathway inhibitor, CRS mice showed a variety of depression-like behaviors, accompanied by enhanced activity of GABAergic neurons in the amygdala projecting to parafascicular nucleus of thalamus. BDNF underexpression occurred in the CRS mice. Overexpressed BDNF activated ERK-CREB-BDNF signaling pathway to alleviate comorbid pain in CRS-induced depression. After intraperitoneal injection of SalB, the depression-like behaviors and pain threshold in CRS mice were alleviated, the effects of which could be eliminated by ERK-CREB-BDNF signaling pathway antagonist. Collectively, SalB inhibits the excitation of GABAergic neurons in the amygdala and activates the ERK-CREB-BDNF signaling pathway through the parafascicular nucleus of thalamus, whereby alleviating comorbid pain in CRS-induced depression in mice.

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Modulation of Neuropathic Pain by Glial Regulation in the Insular Cortex of Rats.

The insular cortex (IC) is known to process pain information. However, analgesic effects of glial inhibition in the IC have not yet been explored. The aim of this study was to investigate pain alleviation effects after neuroglia inhibition in the IC during the early or late phase of pain development. The effects of glial inhibitors in early or late phase inhibition in neuropathic pain were characterized in astrocytes and microglia expressions in the IC of an animal model of neuropathic pain. Changes in withdrawal responses during different stages of inhibition were compared, and morphological changes in glial cells with purinergic receptor expressions were analyzed. Inhibition of glial cells had an analgesic effect that persisted even after drug withdrawal. Both GFAP and CD11b/c expressions were decreased after injection of glial inhibitors. Morphological alterations of astrocytes and microglia were observed with expression changes of purinergic receptors. These findings indicate that inhibition of neuroglia activity in the IC alleviates chronic pain, and that purinergic receptors in glial cells are closely related to chronic pain development.

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Oleanolic acid administration alleviates neuropathic pain after a peripheral nerve injury by regulating microglia polarization-mediated neuroinflammation.

Neuropathic pain caused by a peripheral nerve injury constitutes a great challenge in clinical treatments due to the unsatisfactory efficacy of the current strategy. Microglial activation-mediated neuroinflammation is a major characteristic of neuropathic pain. Oleanolic acid is a natural triterpenoid in food and medical plants, and fulfills pleiotropic functions in inflammatory diseases. Nevertheless, its role in neuropathic pain remains poorly elucidated. In the current study, oleanolic acid dose-dependently suppressed LPS-evoked IBA-1 expression (a microglial marker) without cytotoxicity to microglia, suggesting the inhibitory efficacy of oleanolic acid in microglial activation. Moreover, oleanolic acid incubation offset LPS-induced increases in the iNOS transcript and NO releases from microglia, concomitant with the decreases in pro-inflammatory cytokine transcripts and production including IL-6, IL-1β, and TNF-α. Simultaneously, oleanolic acid shifted the microglial polarization from the M1 phenotype to the M2 phenotype upon LPS conditions by suppressing LPS-induced M1 marker CD16, CD86 transcripts, and enhancing the M2 marker Arg-1 mRNA and anti-inflammatory IL-10 levels. In addition, the LPS-induced activation of TLR4-NF-κB signaling was suppressed in the microglia after the oleanolic acid treatment. Restoring this signaling by the TLR4 plasmid transfection overturned the suppressive effects of oleanolic acid on microglial polarization-evoked inflammation. , oleanolic acid injection alleviated allodynia and hyperalgesia in SNL-induced neuropathic pain mice. Concomitantly, oleanolic acid facilitated microglial polarization to M2, accompanied by inhibition in inflammatory cytokine levels and activation of TLR4-NF-κB signaling. Collectively, these findings confirm that oleanolic acid may ameliorate neuropathic pain by promoting microglial polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype the TLR4-NF-κB pathway, thereby indicating its usefulness as therapeutic intervention in neuropathic pain.

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Association between P2X3 receptors and neuropathic pain: As a potential therapeutic target for therapy.

Neuropathic pain is a common clinical symptom of various diseases, and it seriously affects the physical and mental health of patients. Owing to the complex pathological mechanism of neuropathic pain, clinical treatment of pain is challenging. Therefore, there is growing interest among researchers to explore potential therapeutic strategies for neuropathic pain. A large number of studies have shown that development of neuropathic pain is related to nerve conduction and related signaling molecules. P2X3 receptors (P2X3R) are ATP-dependent ion channels that participate in the transmission of neural information and related signaling pathways, sensitize the central nervous system, and play a key role in the development of neuropathic pain. In this paper, we summarized the structure and biological characteristics of the P2X3R gene and discussed the role of P2X3R in the nervous system. Moreover, we outlined the related pathological mechanisms of pain and described the relationship between P2X3R and chronic pain to provide valuable information for development of novel treatment strategies for pain.

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Inverse Association Between Persistence With Antidepressant Medication and Onset of Chronic Pain in Patients With Depression: A Retrospective Cohort Study.

Despite the known involvement of depression in chronic pain, the association between persistence with and adherence to antidepressant medication and onset of chronic pain in patients with depression remains unclear.

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Sciatic nerve injury rebalances the hypothalamic-pituitary-adrenal axis in rats with persistent changes to their social behaviours.

Increased glucocorticoids characterise acute pain responses, but not the chronic pain state, suggesting specific modifications to the hypothalamic-pituitary-adrenal (HPA)-axis preventing the persistent nature of chronic pain from elevating basal glucocorticoid levels. Individuals with chronic pain mount normal HPA-axis responses to acute stressors, indicating a rebalancing of the circuits underpinning these responses. Preclinical models of chronic neuropathic pain generally recapitulate these clinical observations, but few studies have considered that the underlying neuroendocrine circuitry may be altered. Additionally, individual differences in the behavioural outcomes of these pain models, which are strikingly similar to the range of behavioural subpopulations that manifest in response to stress, threat and motivational cues, may also be reflected in divergent patterns of HPA-axis activity, which characterises these other behavioural subpopulations. We investigated the effects of sciatic nerve chronic constriction injury (CCI) on adrenocortical and hypothalamic markers of HPA-axis activity in the subpopulation of rats showing persistent changes in social interactions after CCI (Persistent Effect) and compared them with rats that do not show these changes (No Effect). Basal plasma corticosterone did not change after CCI and did not differ between groups. However, adrenocortical sensitivity to adrenocorticotropic hormone (ACTH) diverged between these groups. No Effect rats showed large increases in basal plasma ACTH with no change in adrenocortical melanocortin 2 receptor (MC R) expression, whereas Persistent Effect rats showed modest decreases in plasma ACTH and large increases in MC R expression. In the paraventricular nucleus of the hypothalamus of Persistent Effect rats, single labelling revealed significantly increased numbers of corticotropin releasing factor (CRF) +ve and glucocorticoid receptor (GR) +ve neurons. Double-labelling revealed fewer GR +ve CRF +ve neurons, suggesting a decreased hypothalamic sensitivity of CRF neurons to circulating corticosterone in Persistent Effect rats. We suggest that in addition to rebalancing the HPA-axis, the increased CRF expression in Persistent Effect rats contributes to changes in complex behaviours, and in particular social interactions.

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Resolvin D1 alleviates mechanical allodynia via ALX/FPR2 receptor targeted NLRP3/ERK signaling in a neuropathic pain model.

The current study aimed to investigate the role and underlying mechanism of Resolvin D1 (RvD1) alleviating spinal nerve ligation (SNL)-induced neuropathic pain (NP) and its interplay with regulatory cascades of NLRP3 inflammasome. Sprague-Dawley male rat model of SNL-stimulated NP was established, which were pre-treated with different doses of RvD1, WRW4 (ALX/FPR2 inhibitor) or U0126 (ERK inhibitor) for three successive days following the operation. Pain behavior was assessed by measuring changes in the mechanical sensitivity of the hind paws during an observation period of 7 consecutive days. The spinal cord (SC) and dorsal root ganglions (DRGs) tissues were collected on postoperative day 7. Immunohistochemistry (IHC) and western blot were performed to determine the expression levels of NLRP3 inflammasome complex, ALX/FPR2 receptor and extracellular signal-related kinase (ERK). The pro-inflammatory mediators (IL-1β and IL-18) were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that RvD1 could alleviate mechanical allodynia significantly in the SNL-induced NP rat model. Also, RvD1 inhibited the expression of p-ERK, the NLRP3 inflammasomes complex and its corresponding downstream pro-inflammatory mediators which were significantly enhanced in the SC and DRGs of the rat of SNL model. While these changes were partially reversed by pre-administration of WRW4 and further strengthened by co-treated with U0126. Our results suggest that RvD1 dependent on ALX/FPR2 may have an analgesic and anti-inflammatory influence on SNL-induced NP driven by inhibiting NLRP3 inflammasome via ERK signaling pathway. These data also provide strong support for the recent modulation of neuro-inflammatory priming and highlight the potential for specialized pro-resolving mediators (SPMs) as novel therapeutic avenues for NP.

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MiR-128-3p Attenuates the Neurotoxicity in Rats Induced by Isoflurane Anesthesia.

Isoflurane (ISO) has been widely used in clinical anesthesia, and exposure to ISO leads to cognitive dysfunction. Our paper aimed to investigate the effect of miR-128-3p on cognitive impairment, inflammation, and oxidative stress elicited by ISO anesthesia in Sprague-Dawley (SD) rats. The SD rats were treated with ISO to mimic the ISO-injured situation, and the concentration of miR-128-3p was quantified utilizing real-time PCR. The miR-128-3p's impacts in ISO-engendered rat models on the respects of inflammatory condition and oxidative activities were measured by the commercial kits. The Morris water maze test was adopted to measure the neuro-function regarding miR-128-3p. Additionally, the target was tested by the alternation of luciferase activity. The irritation of ISO suppressed miR-128-3p expression in rats, which was enhanced by the injection of miR-128-3p agomir. The adverse roles of ISO on inflammation, oxidative stress, and cognitive disorders were partially abrogated by an increment of miR-128-3p. A miR-128-3p's interconnection with specificity protein 1 (SP1) was pinpointed, and aggrandized mRNA levels of SP1 were found under ISO state. MiR-128 acted as a regulator in ISO damage in the respects of cognition, inflammation, and oxidative stress. The SP1's link of miR-128-3p was showcased.

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Treatment of Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) causes a variety of signs and symptoms, such as low back pain (LBP), intervertebral disc herniation, and spinal stenosis, which contribute to high social and economic costs. IDD results from many factors, including genetic factors, aging, mechanical injury, malnutrition, and so on. The pathological changes of IDD are mainly composed of the senescence and apoptosis of nucleus pulposus cells (NPCs), the progressive degeneration of extracellular matrix (ECM), the fibrosis of annulus fibrosus (AF), and the inflammatory response. At present, IDD can be treated by conservative treatment and surgical treatment based on patients' symptoms. However, all of these can only release the pain but cannot reverse IDD and reconstruct the mechanical function of the spine. The latest research is moving towards the field of biotherapy. Mesenchymal stem cells (MSCs) are regard as the potential therapy of IDD because of their ability to self-renew and differentiate into a variety of tissues. Moreover, the non-coding RNAs (ncRNAs) are found to regulate many vital processes in IDD. There have been many successes in the in vitro and animal studies of using biotherapy to treat IDD, but how to transform the experimental data to real therapy which can apply to humans is still a challenge. This article mainly reviews the treatment strategies and research progress of IDD and indicates that there are many problems that need to be solved if the new biotherapy is to be applied to clinical treatment of IDD. This will provide reference and guidance for clinical treatment and research direction of IDD.

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Time Course and Risk Profile of Work-Related Neck Disability: A Longitudinal Latent Class Growth Analysis.

Given the economic burden of work-related neck pain and disability, it is important to understand its time course and associated risk factors to direct better management strategies. This study aimed to identify the 1-year trajectories of work-related neck disability in a high-risk occupation group such as sonography and to investigate which baseline biopsychosocial factors are associated with the identified trajectories.

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Blended-Learning Pain Neuroscience Education and Exercise in High School Students With Chronic Neck Pain: A Randomized Controlled Trial.

Pain neuroscience education (PNE) and exercise have emerged as potential interventions in adolescents with chronic pain; however, very few studies have explored their effectiveness. Blended-learning approaches combining face-to-face and online educational sessions have also emerged as facilitating methods of health education. This study aimed to compare the effectiveness of exercises and PNE versus exercise alone in adolescents with chronic neck pain.

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Sex-specific differences in the efficacy of traditional low frequency versus high frequency spinal cord stimulation for chronic pain.

Spinal cord stimulation (SCS), an FDA-approved therapy for chronic pain, uses paresthesia (low frequency SCS (LF-SCS)) or paresthesia-free (such as high-frequency SCS (HF-SCS)) systems, providing analgesia through partially-elucidated mechanisms, with recent studies indicating a sexual dimorphism in pain pathogenesis (Bretherton et al., Neuromodulation, 2021; Paller et al., Pain Med 10:289-299, 2009; Slyer et al., Neuromodulation, 2019; Van Buyten et al., Neuromodulation 20:642-649, 2017; Mekhail et al., Pain Pract, 2021). We aim to evaluate SCS therapy sex effects based on paradigm, utilizing visual analog scores (VAS), perceived pain reduction (PPR), and opioid use.

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The Function of the Autonomic Nervous System in Asian Patients With Chronic Migraine.

The pathogenic mechanisms underlying the autonomic nervous system (ANS) dysfunction in patients with chronic migraine (CM) remain unclear. This study investigated the pathogenesis of ANS dysfunction in this population.

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Comprehensive Headache Evaluation and Management for the Otolaryngologist.

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Medical cannabis and stigma: A qualitative study with patients living with chronic pain.

To explore the ways in which stigma is experienced, and what strategies are used to manage stigma among patients using medical cannabis to ease suffering from chronic pain.

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Evaluating value mediation in patients with chronic low-back pain using virtual reality: contributions for empirical research in Value Sensitive Design.

Value Sensitive Design (VSD) is the most well-known method to consider values in design. It consists of three iterative phases of investigation: conceptual, empirical, and technical. Although the approach is promising, the role of empirical research remains unclear. We address two opportunities for extending the role of empirical research in VSD. First, we argue that empirical research enables us to identify values in context. Second, we explain that empirical research enables us to anticipate how technology mediates the values of users. We make our point by means of an empirical study in a real-life controlled experimental context into the value mediation of virtual reality (VR) in patients with chronic low-back pain. Using value-oriented semi-structured interviews with twenty patients, we first analyze what values these patients consider important, and how the values are experienced. The second set of interviews held after all patients used VR four weeks at home, aims to provide insight into value changes as mediated by VR. We end the article by a comparison of our empirical results with previous, often speculative, literature into values in VR. We show that empirical research benefits the VSD process by providing in-depth insight into the effects of context and technology on values and the ability to translate these insights into recommendations for more responsible design and implementation of the technology.

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Lithium use associated with symptom severity in comorbid bipolar disorder I and migraine.

Bipolar disorder (BD) and migraine headaches are frequently comorbid. The common etiological features are unknown, however cortical hyperexcitability (EEG) of migraines, and the report of hyperexcitability in pluripotent stem cell-derived neurons from lithium responsive BD subjects offers a physiological hypothesis of excitable neurons linking these disorders. However, clinical studies suggest that a history of migraine is associated with higher rates of relapse in those with BD taking lithium. Lithium use and history of migraine in this prospective longitudinal study of BD find that lithium use is associated with a greater symptom severity in BD.

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Brain responses to painful electrical stimuli and cognitive tasks interact in the precuneus, posterior cingulate cortex, and inferior parietal cortex and do not vary across the menstrual cycle.

Bidirectional effects between cognition and pain have been extensively reported. Although brain regions involved in cognitive and pain processing seem to partly overlap, it is unknown what specific brain regions are involved in the interaction between pain and cognition. Furthermore, the role of gonadal hormones on these interacting effects has not been examined. This study investigated brain activation patterns of the interaction between pain and cognition over different phases of the naturally occurring menstrual cycle.

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Impact of coronavirus disease 2019 on chronic pain structures: data from French national survey.

The authors evaluated the impact of the first coronavirus disease 2019 pandemic wave on French chronic pain structures (CPSs). An online survey assessed CPS resource allocation, workflow and perceived impact on patient care. All CPS workflow was severely impacted by the reallocation of 42% of specialists. In-person appointments were cancelled by 72% of participants. Follow-up was maintained in 91% of participants (telemedicine). Skills in end-of-life decision-making/counseling were rarely solicited. The perceived impact of the crisis on the experience of patients was high (eight out of ten), with a significant increase in access-to-care delay. CPSs maintained patient follow-up. Special features of CPS specialists were rarely solicited by coronavirus disease 2019 teams experiencing a high workload. Recommendations on optimal CPS resource reallocations have to be standardized in crisis conditions.

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Clinical and neurophysiological effects of progressive movement imagery training for pathological pain.

Movement limitation is a common characteristic of chronic pain such that pain prevents the very movement and activity that is most likely to promote recovery. This is particularly the case for pathological pain states such as complex regional pain syndrome (CRPS). One clinical approach to CRPS that has growing evidence of efficacy involves progressive movement imagery training. Graded Motor Imagery (GMI) targets clinical and neurophysiological effects through a stepwise progression through implicit and explicit movement imagery training, mirror therapy and then functional tasks. Here we review experiences from over 20 years of clinical and research experience with GMI. We situate GMI in terms of its historical underpinnings, the benefits and outstanding challenges of its implementation, its potential application beyond CRPS. We then review the neuropathological targets of GMI and current thought on its effects on neurophysiological biomarkers. Perspective This article provides an overview over experiences made with graded motor imagery training over the last 20 years focussing on the treatment of CRPS. It does both cover the theoretical underpinnings for this treatment approach, biomarkers which indicate potential changes driven by GMI, and experiences for achieving optimal treatment results.

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Infralimbic cortex-medial striatum projections modulate the itch processing.

Itch is an unpleasant sensation that induces the desire to scratch. Except for a sketchy map focusing on neural mechanisms underlying itch processing being drawn at the peripheral and spinal level over the past decade, the brain mechanisms remain poorly understood. Several previous studies indicated that anterior cingulate cortex (ACC) and prelimbic cortex (PrL), two subregions of the medial prefrontal cortex (mPFC) play an important role in regulating itch processing. However, the knowledge about whether infralimbic cortex (IL), another subregion of mPFC, is involved in modulating itch processing remains unclear. Here, we showed that the activity of IL excitatory pyramidal neurons was significantly elevated during itch-related scratching, and pharmacogenetic inhibition of IL pyramidal neurons significantly impaired itch-related scratching. Moreover, IL-medial striatum (MS) projections were verified as a critical neural pathway for modulating itch processing. Therefore, the present study firstly presents the regulatory function of IL pyramidal neurons during itch processing and also reveals that IL-MS projections are involved in modulating the itch processing.

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Inequities in Pain Assessment and Care of Hospitalized Children With Limited English Proficiency.

To examine inequities in pain assessment and management of hospitalized children with limited English proficiency (LEP) as assessed by (1) self-reported pain prevalence and intensity, and (2) nurse-documented pain assessments and analgesia.

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Unsupervised Machine Learning on Motion Capture Data Uncovers Movement Strategies in Low Back Pain.

Chronic low back pain (LBP) is a leading cause of disability and opioid prescriptions worldwide, representing a significant medical and socioeconomic problem. Clinical heterogeneity of LBP limits accurate diagnosis and precise treatment planning, culminating in poor patient outcomes. A current priority of LBP research is the development of objective, multidimensional assessment tools that subgroup LBP patients based on neurobiological pain mechanisms, to facilitate matching patients with the optimal therapies. Using unsupervised machine learning on full body biomechanics, including kinematics, dynamics, and muscle forces, captured with a marker-less depth camera, this study identified a forward-leaning sit-to-stand strategy (STS) as a discriminating movement biomarker for LBP subjects. A forward-leaning STS strategy, as opposed to a vertical rise strategy seen in the control participants, is less efficient and results in increased spinal loads. Inefficient STS with the subsequent higher spinal loading may be a biomarker of poor motor control in LBP patients as well as a potential source of the ongoing symptomology.

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Don’t judge a book by its cover: Exploring low self-reported distress and repressive coping in a pediatric chronic pain population.

Repression has been linked to greater illness, somatic symptoms, and poorer physical health, both in adult and pediatric populations. The current study examined psychological and pain profiles of children with chronic pain who may under-report levels of psychological distress at a first interdisciplinary chronic pain assessment. Children and their caregiver completed measures of psychopathology and pain intensity, while clinicians rated their levels of disability. Based on self-report measures, children were classified as "repressors" (low anxiety/high social desirability) or as "true low anxious" (low anxiety/low social desirability). Groups were then compared on psychological and pain characteristics. Compared to children with true low anxiety, repressors reported lower levels of depressive and somatic symptoms but provided higher ratings on pain intensity, pain-unpleasantness, and self-oriented perfectionism. Caregivers of repressors rated their children as having higher levels of adaptability compared to caregivers of children in the true low anxious group. Groups did not differ on clinician-rated level of disability. Children classified as repressors exhibited different profiles than children classified as having true low anxiety on both psychological outcomes and pain characteristics. Repression may be an important factor to consider for those assessing and treating children with chronic pain.

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Temporomandibular Joint Syndrome from an Ear Versus Dental-Related Standpoint.

Temporomandibular disorders (TMDs) are a prominent reason for visits to medical providers. The presentation of headaches within this population remains a challenging diagnosis, given the prevalence and overlap of symptomatology of both conditions. The literature demonstrates an undeniable association between headaches and TMD. Regardless of causality and etiology, the literature supports that prompt diagnosis and treatment results in improvement or resolution of symptoms, including headaches. Treatment of TMD headaches should begin with conservative measures, including medical management with NSAIDs, heat therapy, and muscle-stretching exercises.

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Headache in Pregnancy.

Headache is a common symptom in pregnancy. The differential diagnosis for headache in pregnancy is broad and includes conditions that range in acuity and severity. Most headaches in pregnancy are migraine or tension-type headaches. However, pregnant women are at an increased risk of vascular causes of headache due to hormone changes and increased hypercoagulability in pregnancy. A careful history, physical examination, and possible diagnostic workup should be performed. Treatment of headache in pregnancy varies according to the etiology, but care should be taken when performing diagnostic studies and considering pharmacologic treatments, given the possible risk to the mother and fetus.

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Utility of Neuroimaging in the Management of Chronic and Acute Headache.

Imaging plays an important role in identifying the cause of the much less common secondary headaches. Such headaches may be caused by a variety of pathologic conditions which can be categorized as intracranial and extracranial. Idiopathic intracranial hypertension imaging findings include "empty sella," orbital changes, and dural venous sinus narrowing. Intracranial hypotension (ICH) is frequently caused by CSF leaks. Imaging findings include loss of the CSF spaces, downward displacement of the brain, as well as dural thickening and enhancement. Severe cases of ICH may result in subdural hematomas. A variety of intracranial and skull base tumors may cause headaches due to dural involvement. Extracranial tumors and lesions that frequently present with headaches include a variety of sinonasal tumors as well as mucoceles. Neurovascular compression disorders causing headaches include trigeminal and glossopharyngeal neuralgia. Imaging findings include displacement and atrophy of the cranial nerve caused by an adjacent arterial or venous structure.

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Exploring Vestibular Assessment in Patients with Headache and Dizziness.

Patients often report symptoms of headache and dizziness concomitantly. Symptoms of dizziness can be explored with a comprehensive vestibular assessment, allowing for the investigation of central and peripheral vestibular system contributions to symptoms of dizziness. Patients who report both symptoms of headache and dizziness demonstrate abnormalities of the vestibular system which can be measured quantitatively. Completion of comprehensive vestibular testing can help to guide diagnosis and strategies for intervention.

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S-Ketamine Pretreatment Alleviates Anxiety-Like Behaviors and Mechanical Allodynia and Blocks the Pro-inflammatory Response in Striatum and Periaqueductal Gray From a Post-traumatic Stress Disorder Model.

This study aims to explore the regulatory effect of S-ketamine on the mechanical allodynia, anxiety-like behaviors and microglia activation in adult male rats exposed to an animal model of post-traumatic stress disorder (PTSD). The rat PTSD model was established by the exposure to single-prolonged stress (SPS), and 1 day later, rats were intraperitoneally injected with 5 mg/kg S-ketamine or normal saline, respectively. Paw withdrawal mechanical threshold was measured 2 days before, and 1, 3, 5, 7, 10, 14, 21 and 28 days after injection to assess mechanical allodynia in the SPS-exposed rats. For anxiety-like behaviors, the open field test and elevated plus maze test were performed at 7 and 14 days after S-ketamine treatment in the SPS-exposed rats, respectively. SPS-induced rats presented pronounced mechanical allodynia and anxiety-like behaviors, which were alleviated by S-ketamine treatment. After behavioral tests, rats were sacrificed for collecting the anterior cingulate cortex (ACC), prefrontal cortex (PFC), dorsal striatum, and periaqueductal gray (PAG). Protein levels of TNF-α, IL-1β, p-NF-κB, and NF-κB in brain regions were examined by Western blot. In addition, microglia activation in each brain region was determined by immunofluorescence staining of the microglia-specific biomarker Iba-1. Interestingly, pro-inflammatory cytokines were significantly upregulated in the dorsal striatum and PAG, rather than ACC and PFC. Activated microglia was observed in the dorsal striatum and PAG as well, and upregulated p-NF-κB was detected in the dorsal striatum. Inflammatory response, phosphorylation of NF-κB and microglia activation in certain brain regions were significantly alleviated by S-ketamine treatment. Collectively, S-ketamine is a promising drug in alleviating mechanical allodynia, anxiety-like behaviors, and pro-inflammatory responses in discrete brain regions in a model of PTSD.

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Headache Diagnosis in Children and Adolescents.

Pediatric headache is a common medical complaint managed across multiple subspecialties with a myriad of unique factors (clinical presentation and disease phenotype) that make accurate diagnosis particularly elusive. A thorough understanding of the stepwise approach to headache disorders in children is essential to ensure appropriate evaluation, timely diagnosis, and efficacious treatment. This work aims to review key components of a comprehensive headache assessment as well as discuss primary and secondary headache disorders observed in children, with a particular focus on clinical pearls and "red flag" symptoms necessitating ancillary diagnostic testing.

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Idiopathic Intracranial Hypertension: Implications for the Otolaryngologist.

Idiopathic intracranial hypertension (IIH) is a triad of headaches, visual changes, and papilledema in the absence of a secondary cause for elevated intracranial pressure. There is an association with obesity, and the incidence is rising in parallel with the obesity epidemic. Sometimes these patients present to an otolaryngologist with complaints like tinnitus, dizziness, hearing loss, and otorrhea or rhinorrhea from cerebrospinal fluid leak. IIH diagnosis in conjunction with neurology and ophthalmology, including neuroimaging and lumbar puncture with opening pressure, is key to managing of this condition. Otolaryngologists should recognize IIH as a possible diagnosis and initiate appropriate referrals and treatment.

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A Review of Medical and Surgical Options for the Treatment of Facial Pain.

Facial pain is a common medical complaint that is easily misdiagnosed. As a result, this pain often goes mistreated. Despite this, there are a variety of pharmacologic, surgical, and neuromodulatory options for the treatment of facial pain. In this review, the authors detail the forms of facial pain and their treatment options. They discuss the common medications used in the first-line treatment of facial pain and the second-line surgical and neuromodulatory options available to patients when pharmacologic options fail.

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The Role of the Otolaryngologist in the Evaluation and Management of Headache.

Headaches are a global health problem and are encountered by a variety of specialties, including otolaryngologists. These patients can present as a challenge, but an understanding of primary and secondary headache disorders and the accompanying broad differential diagnosis is critical. For secondary headache disorders, a differential diagnosis categorized by anatomic location can help organize the evaluation of these patients, which can then be narrowed by the history and examination findings. Additional ancillary tests such as laboratories and imaging can further aid in diagnosis but are not always necessary.

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Engaging with EPIO, a digital pain self-management program: a qualitative study.

Chronic pain conditions entail significant personal and societal burdens and improved outreach of evidence-based pain self-management programs are needed. Digital cognitive-behavioral self-management interventions have shown promise. However, evidence is still scarce and several challenges with such interventions for chronic pain exist. Exploring patients' experiences and engagement with digital interventions may be an essential step towards developing meaningful digital self-management interventions for those living with chronic pain.

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Peripheral sensitization is demonstrated in subacromial pain syndrome, with central sensitization found only in females.

The objective of this study was to explore whether hypersensitivity in patients with subacromial pain syndrome manifests purely as localized peripheral sensitization or central sensitization, is influenced by the presence of subacromial pain, and presents similarly in male and female patients. Pressure pain threshold was assessed in both a patient cohort with unilateral subacromial pain syndrome and an uninjured matched control group. Control subjects were tested once, while patients were assessed at baseline and after an almost instantaneous reduction in pain arising from an anesthetic injection in patients. Patients received a subacromial injection consisting of both anesthetics (3 cc of 2% lidocaine and 6 cc 0.5% Marcaine with Epinephrine) and a corticosteroid agent (1 cc DepoMedrol). Patients demonstrated hypersensitivity across the involved shoulder only, providing evidence for peripheral sensitization. There were trends for hypersensitivity across remote joints, however when separated by sex, only female patients demonstrated both peripheral and central sensitization. Immediate pain reduction had no influence on hypersensitivity in the short-term. CLINICAL SIGNIFICANCE -: Neuropathic components are likely present in some patients with subacromial pain syndrome, and female patients may be particularly at risk for presenting with neuropathic pain. These findings are applicable towards understanding the heterogeneous etiology underlying subacromial pain syndrome and informing clinical management. This article is protected by copyright. All rights reserved.

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Human Synovial Fluid Interleukin-6, but not Type II Collagen Breakdown, Positively Correlated with Pain After ACL Injury and Reconstruction.

Anterior cruciate ligament (ACL) injury initiates a biochemical cascade thought to contribute to the onset and progression of posttraumatic osteoarthritis (PTOA). Interleukin-1ß (IL-1ß), IL-6, and C-telopeptide fragments of type II collagen (CTX-II) are implicated in joint inflammation and cartilage degradation following ACL injury; however, their association with pain is still being explored. The purpose of this study was to evaluate the associations between synovial fluid concentrations of IL-1ß, IL-6, and CTX-II with pain following ACL injury and reconstruction. We hypothesized that greater IL-1ß, IL-6, and CTX-II would correlate with greater Pain Visual Analogue Scale (VAS) scores. This was a secondary analysis of 23 patients (mean age=18.4 y, BMI=27.4, 13 Females/10 Males) with acute ACL tears who participated in a pilot randomized trial. Synovial fluid and VAS scores were collected on the day of initial presentation, at ACL reconstruction, and 1- and 4-weeks after surgery. Synovial fluid concentrations of IL-1ß, IL-6, and CTX-II were assessed using enzyme linked immunoabsorbent assays (ELISA), and repeated measures correlations were used to assess the relationships between pain and synovial IL-1ß, IL-6, or CTX-II after ACL injury and reconstruction. Pain was positively correlated with synovial fluid IL-6 concentrations (r=0.52, p<0.001); however, pain was inversely correlated with CTX-II (r= -0.39, p=0.002). IL-1ß had no significant correlation with pain. Statement of Clinical Relevance PTOA has been described as a "silent killer" and these results suggest that early PTOA may have pro-inflammatory pathways that are not primarily associated with pain but still lead to progressive cartilage loss. This article is protected by copyright. All rights reserved.

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Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE).

Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a multisystem illness characterized by extreme muscle fatigue associated with pain, neurocognitive impairment, and chronic inflammation. Despite intense investigation, the molecular mechanism of this disease is still unknown. Here we demonstrate that autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy. A Thioflavin T-based protein aggregation assay, array screening for autophagy-related factors, densitometric analyses, and confirmation with ELISA revealed that the level of ATG13 was strongly elevated in serum samples of ME/CFS patients compared to age-matched controls. Moreover, our microglia-based oxidative stress response experiments indicated that serum samples of ME/CFS patients evoke the production of reactive oxygen species (ROS) and nitric oxide in human HMC3 microglial cells, whereas neutralization of ATG13 strongly diminishes the production of ROS and NO, suggesting that ATG13 plays a role in the observed stress response in microglial cells. Finally, an in vitro ligand binding assay provided evidence that ATG13 employs the Receptor for Advanced Glycation End-products (RAGE) to stimulate ROS in microglial cells. Collectively, our results suggest that an impairment of autophagy following the release of ATG13 into serum could be a pathological signal in ME/CFS.

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Opioid-induced hyperalgesia: is it a clinically relevant phenomenon?

The potential for the development of opioid-induced hyperalgesia (OIH) provokes debate about whether long-term treatment with opioids is advisable and effective. If OIH develops during acute administration, will continuation of opioids actually make the pain worse? Hence, it is not surprising that OIH is part of the rationale used to promote deprescribing opioids in patients with chronic pain. But is there evidence that OIH is a clinically relevant phenomenon? This Commentary examines the evidence for OIH in randomized clinical trials in both the acute and chronic settings. Of critical importance in such an assessment is a trial design capable of differentiating OIH, tolerance, withdrawal-mediated pain sensitivity and worsening of the disease. However, studies published to date that purport to give evidence of OIH via experimentally induced pain all lack the rigour needed to differentiate these phenomena. Patient-reported measures of pain and analgesic consumption in these trials are not consistent with the presence of clinically significant OIH. At present, there is insufficient evidence from well-designed clinical trials that OIH is a clinically relevant phenomenon. Hence, while there are other reasons to avoid long-term use of opioids, the potential for the development of hyperalgesia during chronic opioid treatment is not a sound rationale for deprescribing these drugs in patients with chronic pain.

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Cannabis for Rheumatic Disease Pain: a Review of Current Literature.

Changing attitudes about marijuana have led to an increase in use of medicinal marijuana, especially for painful chronic conditions. Patients ask rheumatologists for guidance on this topic. This review provides up-to-date information on the safety and efficacy of medicinal cannabis for rheumatic disease pain.

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Health-related quality of life of Malaysian patients with chronic non-malignant pain and its associated factors: a cross-sectional study.

Chronic pain has a major impact on a patient's quality of life, affecting physical and psychological functioning. It has debilitating consequences on social and economic aspects too. This study aimed to explore the status of health-related quality of life (HRQoL) of Malaysian patients suffering from chronic non-malignant pain.

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Vestibular Migraine: Clinical Aspects and Pathophysiology.

VM is a common yet debilitating migraine variant that has taken many monikers in the past. As a relatively new diagnostic entity, public and provider awareness of this disorder can be improved. Symptoms include vertigo episodes in addition to photophobia, phonophobia, nausea, and headache. Diagnosis is primarily based on clinical history as pathognomonic signs via testing are not reliable. Standardized treatment algorithms have yet to be created and current recommendations have been adopted from migraine guidelines.

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Analgesic effect of electroacupuncture on bone cancer pain in rat model: the role of peripheral P2X3 receptor.

Upregulation of P2X3 receptor (P2X3R) has been strongly implicated in nociceptive signaling including bone cancer pain (BCP). The present study, using rat bone cancer model, aimed to explore the role of P2X3R in regulating rat pain behavior under the intervention of electroacupuncture (EA). The BCP model was successfully established by injection with MRMT-1 breast cancer cell into the medullary cavity of left tibia for 3 × 10 cells/3 μL PBS in rats as revealed by obvious bone destruction, decreased paw withdrawal thresholds (PWTs), and reduced paw withdrawal latencies (PWLs). Western blot analyses showed that P2X3R expression was significantly upregulated in ipsilateral lumbar 4-6 (L4-6) dorsal root ganglia (DRG), but the difference not seen in spinal cord dorsal horn (SCDH). With the in-depth study of P2X3R activation, we observed that intrathecal injection of P2X3R agonist α,β-meATP aggravated MRMT-1 induced BCP, while injection of P2X3R inhibitor A-317491 alleviated pain. Subsequently, we demonstrated that BCP induced mechanical allodynia and thermal hyperalgesia were attenuated after EA treatment. Under EA treatment, total P2X3R protein expression in ipsilateral DRGs was decreased, and it is worth mentioning that decreased expression of P2X3R membrane protein, which indicated that both the expression and membrane trafficking of P2X3R were inhibited by EA. The immunofluorescence assay showed that EA stimulation exerted functions by reducing the expression of P2X3R-positive cells in ipsilateral DRGs of BCP rats. Ca imaging analysis revealed that the EA stimulation decreased the percentage of α,β-meATP responsive neurons in DRGs and inhibited calcium influx. Notably, the inhibitory effect of EA on mechanical allodynia and nociceptive flinches was abolished by intrathecal injection of α,β-meATP. These findings demonstrated EA stimulation ameliorated mechanical allodynia and thermal hyperalgesia in rat model of MRMT-1-induced BCP. EA exerts analgesic effect on BCP by reducing the overexpression and functional activity of P2X3R in ipsilateral DRGs of BCP rats. Our work first demonstrates the critical and overall role of P2X3R in EA's analgesia against peripheral sensitization of MRMT-1-induced BCP and further supports EA as a potential therapeutic option for cancer pain in clinic.

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