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Papers: 4 Jul 2020 - 10 Jul 2020

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Irritant-evoked activation and calcium modulation of the TRPA1 receptor.

The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, including small volatile environmental toxicants and endogenous algogenic lipids. TRPA1 is also a 'receptor-operated' channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch, making it an attractive target for novel analgesic therapies. However, the mechanisms by which TRPA1 recognizes and responds to electrophiles or cytoplasmic second messengers remain unknown. Here we use strutural studies and electrophysiology to show that electrophiles act through a two-step process in which modification of a highly reactive cysteine residue (C621) promotes reorientation of a cytoplasmic loop to enhance nucleophilicity and modification of a nearby cysteine (C665), thereby stabilizing the loop in an activating configuration. These actions modulate two restrictions controlling ion permeation, including widening of the selectivity filter to enhance calcium permeability and opening of a canonical gate at the cytoplasmic end of the pore. We propose a model to explain functional coupling between electrophile action and these control points. We also characterize a calcium-binding pocket that is highly conserved across TRP channel subtypes and accounts for all aspects of calcium-dependent TRPA1 regulation, including potentiation, desensitization and activation by metabotropic receptors. These findings provide a structural framework for understanding how a broad-spectrum irritant receptor is controlled by endogenous and exogenous agents that elicit or exacerbate pain and itch.

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Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models.

Cyclin-dependent-like kinase 5 () gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay, and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognized anamnestic deficiency in pain perception. Consistent with a role in nociception, we found that CDKL5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in induced pluripotent stem cell (iPS)-derived human nociceptors. CDKL5-deficient mice display defective epidermal innervation, and conditional deletion of in DRG sensory neurons impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, CDKL5 interacts with calcium/calmodulin-dependent protein kinase II α (CaMKIIα) to control outgrowth and transient receptor potential cation channel subfamily V member 1 (TRPV1)-dependent signaling, which are disrupted in both mutant murine DRG and human iPS-derived nociceptors. Together, these findings unveil a previously unrecognized role for CDKL5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.

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A transcriptional toolbox for exploring peripheral neuro-immune interactions.

Correct communication between immune cells and peripheral neurons is crucial for the protection of our bodies. Its breakdown is observed in many common, often painful conditions, including arthritis, neuropathies and inflammatory bowel or bladder disease. Here, we have characterised the immune response in a mouse model of neuropathic pain using flow cytometry and cell-type specific RNA sequencing (RNA-seq). We found few striking sex differences, but a very persistent inflammatory response, with increased numbers of monocytes and macrophages up to 3½ months after the initial injury. This raises the question of whether the commonly used categorisation of pain into "inflammatory" and "neuropathic" is one that is mechanistically appropriate. Finally, we collated our data with other published RNA-seq datasets on neurons, macrophages and Schwann cells in naïve and nerve injury states. The result is a practical web-based tool for the transcriptional data-mining of peripheral neuroimmune interactions.

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Quantitative differences in neuronal subpopulations between mouse and human dorsal root ganglia demonstrated with RNAscope in situ hybridization.

Next generation transcriptomics in combination with imaging-based approaches have emerged as powerful tools for the characterization of dorsal root ganglion (DRG) neuronal subpopulations. The mouse DRG has been well-characterized by many independently conducted studies with convergent findings, but few studies have directly compared expression of population markers between mouse and human. This is important because of our increasing reliance on the mouse as a preclinical model for translational studies. While calcitonin gene-related peptide (CGRP) and P2X purinergic ion channel type 3 receptor (P2X3R) have been used to define peptidergic and non-peptidergic nociceptor subpopulations, respectively, in mouse DRG, these populations may be different in other species. To directly test this, as well as a host of other markers, we used multiplex RNAscope in-situ hybridization to elucidate the distribution of a multitude of unique and classic neuronal mRNAs in peptidergic (CGRP expressing) and non-peptidergic (P2X3R expressing) nociceptor subpopulations in mouse and human DRG. We found a large overlapping CGRP and P2X3R neuronal subpopulation in human, lumbar DRG that was not present in mouse. We also found differential expression in a variety of mRNAs for TRP-channels, cholinergic receptors, potassium channels, sodium channels, other markers/targets. These data offer insights into the spatial and functional organization of neuronal cell subpopulations in the rodent and human DRG and support the idea that sensory system organizational principles are likely different between both species.

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Selective amplification of ipRGC signals accounts for interictal photophobia in migraine.

Second only to headache, photophobia is the most debilitating symptom reported by people with migraine. While the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to play a role, how cone and melanopsin signals are integrated in this pathway to produce visual discomfort is poorly understood. We studied 60 people: 20 without headache and 20 each with interictal photophobia from migraine with or without visual aura. Participants viewed pulses of spectral change that selectively targeted melanopsin, the cones, or both and rated the degree of visual discomfort produced by these stimuli while we recorded pupil responses. We examined the data within a model that describes how cone and melanopsin signals are weighted and combined at the level of the retina and how this combined signal is transformed into a rating of discomfort or pupil response. Our results indicate that people with migraine do not differ from headache-free controls in the manner in which melanopsin and cone signals are combined. Instead, people with migraine demonstrate an enhanced response to integrated ipRGC signals for discomfort. This effect of migraine is selective for ratings of visual discomfort, in that an enhancement of pupil responses was not seen in the migraine group, nor were group differences found in surveys of other behaviors putatively linked to ipRGC function (chronotype, seasonal sensitivity, presence of a photic sneeze reflex). By revealing a dissociation in the amplification of discomfort vs. pupil response, our findings suggest a postretinal alteration in processing of ipRGC signals for photophobia in migraine.

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An Emerging Role for Prolactin in Female-Selective Pain.

Women experience many pain conditions more frequently when compared with men, but the biological mechanisms underlying sex differences in pain remain poorly understood. In particular, little is known about possible sex differences in peripheral nociceptors, the fundamental building blocks of pain transmission. Emerging evidence reveals that prolactin (PRL) signaling at its cognate prolactin receptor (PRLR) in primary afferents promotes nociceptor sensitization and pain in a female-selective fashion. In this review, we summarize recent progress in understanding the female-selective role of PRL/PRLR in nociceptor sensitization and in pathological pain conditions, including postoperative, inflammatory, neuropathic, and migraine pain, as well as opioid-induced hyperalgesia. The clinical implications of the peripheral PRL/PRLR system for the discovery of new therapies for pain control in women are also discussed.

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Spinal Wnt5a plays a key role in spinal dendritic spine remodeling in neuropathic and inflammatory pain models and in the pro-algesic effects of peripheral Wnt3a.

Wnt signaling represents a highly versatile signaling system, which plays critical roles in developmental morphogenesis as well as synaptic physiology in adult life and is implicated in a variety of neural disorders. Recently, we demonstrated that Wnt3a is able to recruit multiple non-canonical signaling pathways to alter peripheral sensory neuron function in a nociceptive modality-specific manner. Furthermore, several studies recently reported an important role for Wnt5a acting via canonical and non-canonical signaling in spinal processing of nociception in a number of pathological pain disorders. Here, using diverse molecular, genetic, and behavioral approaches in mouse models of pain , we report a novel role for Wnt5a signaling in nociceptive modulation at the structural level. In models of chronic pain, using male and female mice, we found that Wnt5a is released spinally from peripheral sensory neurons, where it recruits the tyrosine kinase receptors Ror2 and Ryk to modulate dendritic spine rearrangement. Blocking the Wnt5a-Ryk/Ror2 axis in spinal dorsal horn neurons prevented activity-dependent dendritic spine remodeling and significantly reduced mechanical hypersensitivity induced by peripheral injury as well as inflammation. Moreover, we observed that peripheral Wnt3a signaling triggers the release of Wnt5a in the spinal cord, and inhibition of spinal Wnt5a signaling attenuates the functional impact of peripheral Wnt3a on nociceptive sensitivity. In conclusion, this study reports a novel role for the Wnt signaling axis in coordinating peripheral and spinal sensitization and shows that targeting Wnt5a-Ryk/ROR2 signaling alleviates both structural and functional mechanisms of nociceptive hypersensitivity in models of chronic pain There is a major need to elucidate molecular mechanisms underlying chronic pain disorders in order to develop novel therapeutic approaches. Wnt signaling represents a highly versatile signaling system, which plays critical roles during development and adult physiology, and it was implicated in several diseases, included chronic pain conditions. Using mouse models, our study identifies a novel role for Wnt5a signaling in nociceptive modulation at the spinal cord level. We observed that Wnt5a recruits Ror2 and Ryk receptors to enhance dendritic spine density, leading to nociceptive sensitization. Blocking the Wnt5a-Ryk/Ror2 interaction in the spinal dorsal horn prevented spine remodeling and significantly reduced inflammatory and neuropathic hypersensitivity. These findings provide proof-of-concept for targeting spinal Wnt signaling for alleviating nociceptive hypersensitivity .

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One-year sustained efficacy of erenumab in episodic migraine: Results of the STRIVE study.

To assess efficacy and tolerability of 1-year erenumab treatment in patients with episodic migraine.

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Uncovering the analgesic effects of a pH-dependent mu-opioid receptor agonist using a model of non-evoked ongoing pain.

Currently, opioids targeting mu-opioid receptors (MOR) are the most potent drugs for acute and cancer pain. However, opioids produce adverse side effects such as constipation, respiratory depression, or addiction potential. We recently developed (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), a compound that does not evoke central or intestinal side effects due to its selective activation of MOR at low pH in peripheral injured tissues. While we demonstrated that NFEPP effectively abolishes injury-induced pain, hyperalgesia and allodynia in rodents, the efficacy of NFEPP in non-evoked ongoing pain remains to be established. Here we examined reward, locomotor activity and defecation in rats with complete Freund's adjuvant-induced paw inflammation to compare fentanyl's and NFEPP's potentials to induce side effects and to inhibit spontaneous pain. We demonstrate that low, but not higher doses of NFEPP produce conditioned place preference but not constipation or motor disturbance, in contrast to fentanyl. Using a peripherally restricted antagonist we provide evidence that NFEPP-induced place preference is mediated by peripheral opioid receptors. Our results indicate that a low dose of NFEPP produces reward by abolishing spontaneous inflammatory pain.

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The Golden Half Hour in Chronic Pediatric Pain-Feedback as the First Intervention.

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Individuals with chronic pain have the same response to placebo analgesia as healthy controls in terms of magnitude and reproducibility.

It is unclear whether a diagnosis of chronic pain is associated with an increase or decrease in the placebo response. The aim of this study was to use an experimental placebo conditioning paradigm to test if expectancy for pain relief impacts on acute pain perception in individuals with a chronic pain diagnosis of osteoarthritis (OA) or fibromyalgia (FM), compared to healthy individuals (HI). An inert cream was applied to the dominant forearm of participants (60 OA, 79 FM and 98 HI), randomly assigned to either a placebo or control group. In both groups an inactive cream was applied to the dominant forearm. The placebo group was told this may or may not be a local anaesthetic cream, while the control group was told the cream was inactive. Laser pain was delivered, and numerical pain intensity ratings collected before, during and after cream application, along with expectation of pain relief and anxiety. The procedure was repeated two weeks later to assess reproducibility. There was a significant reduction in pain in the placebo group, independent of clinical diagnosis. Diagnostic groups (OA,FM,HI) did not differ in their magnitude of placebo analgesia or expectancy of pain relief. The results were similar in the repeat session. The results demonstrate that individuals with chronic pain respond to experimental placebo analgesia in a similar and reproducible manner as healthy individuals, despite higher levels of psychological co-morbidity. This has implications for utilising placebo analgesia in the treatment of chronic pain.

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Medication overuse headache: Divergent effects of new acute antimigraine drugs.

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Understanding the relationship between features associated with pain-related disability in people with painful Temporomandibular Disorder (TMD): an exploratory structural equation modeling approach.

Pain-related disability is a multi-faceted construct that refers to the impact of pain on an individual's capacity to fulfill their self-defined and social roles. This research examined the relationship between clinical, psychological and pain sensitivity factors and pain-related disability among adults with chronic temporomandibular disorder (TMD). We analyzed data from a cross-sectional community-based sample of 1088 men and women with chronic TMD. We first constructed and tested a measure of pain-related disability (i.e., pain impact) including a variable assessing presenteeism, created measurement models of jaw limitation, psychological unease (negative affect, somatic symptoms, catastrophizing), and experimental pain sensitivity (e.g., pressure pain threshold, thermal tolerance and mechanical pressure pain threshold). Subsequently, latent variables were combined in a structural equation model. Participants (n=1088) were 18-44 years old (mean 29.2, SD+7.8) whose chronic TMD had persisted, on average, for 6.9 years (SD+6.4). A model of pain related disability, jaw limitation, and psychological unease was created and refined with exploratory model revisions to account for correlation among variables. Estimation of the final model indicated excellent fit with the data (RMSEA=0.048, RMSEA 90% confidence interval (CI) 0.043, 0.053, CFI=0.956, SRMR=0.040). Jaw functional limitation and psychological unease was strongly related to pain-related disability. Experimental pain sensitivity was removed from our model due to weak direct effect and the burden of performing experimental pain sensitivity testing in a clinical setting. The final model explained 78% of the variance in pain-related disability.

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Substance P-expressing neurons in the superficial dorsal horn of the mouse spinal cord: insights into their functions and their roles in synaptic circuits.

The tachykinin peptide substance P (SP) is expressed by many interneurons and some projection neurons in the superficial dorsal horn of the spinal cord. We have recently shown that SP-expressing excitatory interneurons in lamina II correspond largely to a morphological class known as radial cells. However, little is known about their function, or their synaptic connectivity. Here we use a modification of the Brainbow technique to define the excitatory synaptic input to SP radial cells. We show that around half of their excitatory synapses (identified by expression of Homer) are from boutons with VGLUT2, which are likely to originate mainly from local interneurons. The remaining synapses presumably include primary afferents, which generally have very low levels of VGLUT2. Our results also suggest that the SP cells are preferentially innervated by a population of excitatory interneurons defined by expression of green fluorescent protein under control of the gene for gastrin-releasing peptide, and that they receive sparser input from other types of excitatory interneuron. We show that around 40% of lamina I projection neurons express Tac1, the gene encoding substance P. Finally, we show that silencing Tac1-expressing cells in the dorsal horn results in a significant reduction in reflex responses to cold and radiant heat, but does not affect withdrawal to von Frey hairs, or chloroquine-evoked itch.

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A genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine.

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (N/N = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, r = 0.11, P = 3.56 × 10) and systolic BP (SBP, r = 0.06, P = 0.01), but not pulse pressure (PP, r = -0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15-1.25]/10 mmHg; P = 5.57 × 10) on migraine than SBP (1.05 [1.03-1.07]/10 mmHg; P = 2.60 × 10) and a corresponding opposite effect for PP (0.92 [0.88-0.95]/10 mmHg; P = 3.65 × 10). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine.

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The role of microRNAs in neurons and neuroimmune communication in the dorsal root ganglia in chronic pain.

Despite being a life-restricting condition, chronic pain remains poorly treated. A better understanding of the underlying mechanisms of chronic pain and thence development of innovative targets is therefore essential. Recently we have started to elucidate the importance of the role of microRNAs (miRs) in preclinical chronic pain. miRs are small, non-coding RNAs that regulate genes including those involved in nociceptive signalling. MiRs can exert their effects both intracellularly and extracellularly, the latter of which requires that they are released either as naked species or packaged in exosomes. Here we discuss changes in miR expression that occur in the dorsal root ganglia in murine models of chronic pain. We consider the downstream targets of changes in miR expression, including voltage-gated ion channels, as well as discuss extracellular consequences such as changes in macrophage phenotype that constitute of means by which neuron-immune cell crosstalk occurs. Such miR-mediated intracellular communication could provide a novel target for the treatment of chronic pain, which would be most effective if tailored to the specific cause of pain. Indeed, we conclude by reviewing evidence for the involvement of miRs in clinical cases of chronic pain, supporting the notion that tailored, miR-targeted therapies could prove to be an effective new strategy for the treatment of chronic pain clinically.

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Does a screening trial for spinal cord stimulation in patients with chronic pain of neuropathic origin have clinical utility and cost-effectiveness (TRIAL-STIM)? a randomised controlled trial.

Spinal cord stimulation (SCS) is an established treatment of chronic neuropathic pain. Although a temporary SCS screening trial is widely used to determine whether a patient should receive permanent SCS implant, its evidence base is limited. We aimed to establish the clinical utility, diagnostic accuracy, and cost-effectiveness of an SCS screening trial. A multicentre single-blind, parallel two-group randomised controlled superiority trial was undertaken at three centres in United Kingdom. Patients were randomised 1:1 to either SCS screening trial strategy (TG) or no trial screening strategy (NTG). Treatment was open label, but outcome assessors were masked. The primary outcome measure was numerical rating scale (NRS) pain at six-months follow-up. Between June 2017 and September 2018, 105 participants were enrolled and randomised (TG=54, NTG=51). Mean NRS pain decreased from 7.47 at baseline (before SCS implantation) to 4.28 at 6-months in TG and from 7.54 to 4.49 in NTG (mean group difference: 0.2, 95% CI: -1.2 to 0.9, p=0.89). We found no difference between TG and NTG in the proportion of pain responders or other secondary outcomes. SCS screening trial had a sensitivity of 100% (95% CI: 78 to 100) and specificity of 8% (95% CI: 1 to 25). The mean incremental cost-effectiveness ratio of TG versus NTG was £78,895 per additional quality-adjusted life-year (QALY) gained. In conclusion, although the SCS screening trial may have some diagnostic utility, there was no evidence that an SCS screening trial strategy provides superior patient outcomes or is cost-effective compared to a no trial screening approach.

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Topical Application of ASN008, a Permanently-charged Sodium Channel Blocker, Shows Robust Efficacy, a Rapid Onset and Long Duration of Action in a Mouse Model of Pruritus.

The sensation of pruritus, or itch, is associated with a variety of skin and medical disorders. Itch is transmitted through afferent C-fibers, and sodium channels play a key role in the transmission process. Local anesthetics, which block sodium channels, are used topically to treat itch, but generally have a short duration of action and are not selective for afferent nerves underlying the itch sensation. Accordingly, there is a substantial unmet need for safe, efficacious, long-acting treatments for chronic pruritus, including non-histaminergic itch. We investigated the dose-response, time to onset and duration of action of ASN008 topical gel, which targets small afferent sodium channels, in a murine model of pruritus in which scratching behavior is induced by intradermal injection of chloroquine into the nape of the neck of C57BL/6 mice. Topical application of ASN008 gel resulted in a concentration-dependent reduction of scratching behavior. Onset of action was ≤ 1 hour and duration of scratching inhibition was 15-24 hours. In a further study involving once-daily application for 5 days with chloroquine challenge on day 5, treatment with ASN008 gel again resulted in a concentration-dependent reduction of chloroquine-induced scratching, even when the gel was removed 3 hours after each daily application. In conclusion, topical ASN008 gel produces a dose-dependent reduction of scratching in a mouse model of pruritus, with a rapid onset and long duration of action, and may prove to be an effective, once-daily treatment for a variety of pruritic conditions in humans, including non-histaminergic itch. SIGNIFICANCE STATEMENT: ASN008 gel produces a dose-dependent reduction of scratching in a mouse model of pruritus, with a rapid onset and long duration of action, and may prove to be an effective, once or twice-daily treatment for a variety of pruritic conditions in humans, including non-histaminergic itch. ASN008 topical gel is currently under investigation in Phase 1 clinical studies to evaluate safety, tolerability, pharmacokinetics and preliminary anti-pruritic efficacy in atopic dermatitis patients (ClinicalTrials.gov ID: NCT03798561).

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Ubrogepant does not induce latent sensitization in a preclinical model of medication overuse headache.

Ubrogepant, a small-molecule calcitonin gene-related peptide receptor antagonist, was recently approved as an oral medication for the acute treatment of migraine. This study aimed to determine whether ubrogepant shows efficacy in a preclinical model of migraine-like pain and whether repeated oral administration of ubrogepant induces latent sensitization relevant to medication overuse headache in rats.

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Trial of Nemolizumab and Topical Agents for Atopic Dermatitis with Pruritus.

Nemolizumab is a subcutaneously administered humanized monoclonal antibody against interleukin-31 receptor A, which is involved in pruritus and inflammation in atopic dermatitis. In phase 2 studies, nemolizumab lessened the severity of atopic dermatitis.

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Central neurobiological effects of physical exercise in individuals with chronic musculoskeletal pain: a systematic review.

Primary objectives: to investigate the central neurobiological effects (using MRI) of physical exercise in individuals with chronic pain. Secondary objectives: (1) to investigate the associations between central changes and clinical outcomes and (2) to investigate whether different types and dosages of physical exercise exert different central changes.

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Transcranial direct current stimulation and visual illusion effect according to sensory phenotypes in patients with spinal cord injury and neuropathic pain.

Treatment of neuropathic pain (NP) in patients with spinal cord injury (SCI) remains a major challenge. The aim of the present study is to investigate if the effect of transcranial direct current stimulation (tDCS) combined with visual illusion (VI), following a previously published protocol, has differential effects on pain-related sensory symptoms according to sensory phenotypes profiles. One hundred and thirty SCI patients with NP participated in this open-label trial. Sixty-five patients were given a daily 20-minutes combined treatment of tDCS and VI for 2 weeks. Sixty-five patients served as a control group. Clinical assessment was performed before and 2 weeks later, by using Neuropathic Pain Symptom Inventory (NPSI), Brief Pain Inventory (BPI), and Patient Health Questionnaire-9 (PHQ-9). There was significant improvement in the combined treatment group according to NPSI, BPI and PHQ-9, but no changes in the control group. Following a cluster analysis of NPSI items at baseline assessment, five subgroups of patients with different pain-related characteristics were identified among the treated group, although differences between clusters were not significant. There was also improvement in mood, sleep quality, and enjoyment of life in the treated group. Despite a reduction of NP with the combined treatment, the analysis of sensory phenotype pain profiles does not provide a predictive value regarding the analgesic results of this combined neuromodulatory treatment. Perspective In this article we confirm the analgesic effect of a combined neuromodulatory therapy, transcranial direct current stimulation associated with visual illusion in patients with NP after an SCI. We have identified five clusters of NP with distinct sensory phenotypes, but there was not any specific sensory phenotype cluster that significantly responded to the combined therapy better than the other.

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Systemic inflammatory markers in neck pain: a systematic review with meta-analysis.

Mechanisms underpinning symptoms in non-traumatic neck pain (NTNP) and whiplash-associated disorder (WAD) are not comprehensively understood. There is emerging evidence of systemic inflammation in musculoskeletal pain conditions, including neck and back pain. The aim of this systematic review was to determine if raised blood inflammatory markers are associated with neck pain.

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Predictors and mediators of outcome in cognitive behavioral therapy for chronic pain: the contributions of psychological flexibility.

There is now a consensus in the literature that future improvements in outcomes obtained from cognitive behavioral therapy (CBT) for chronic pain will require research to identify patient and treatment variables that help explain outcomes. The first aim of this study was to assess whether pre-treatment scores on measures of psychological (in)flexibility, acceptance, committed action, cognitive (de)fusion, and values-based action predict outcomes in a multidisciplinary, multicomponent, group-based CBT program for adults with chronic pain. The second aim was to assess whether change scores on these same measures mediate outcomes in the treatment program. Participants were 232 people attending treatment for chronic pain. Of the psychological flexibility measures, only pre-treatment scores on the psychological inflexibility scale predicted outcomes; higher scores on this measure were associated with worse outcomes. However, change scores on each of the psychological flexibility measures separately mediated outcomes. The efficacy of CBT for chronic pain may be improved with a greater focus on methods that increase psychological flexibility.

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The influence of friendship on migraine in young adolescents: A social network analysis.

The current study explored whether the chances of having migraine are influenced by a youth's friendship with a migraineur.

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TRESK and TREK-2 two pore-domain potassium channel subunits form functional heterodimers in primary somatosensory neurons.

Two-pore domain potassium channels (K2P) are the major determinants of the background potassium conductance. They play a crucial role in setting the resting membrane potential and regulating cellular excitability.  These channels form homodimers, however, a few examples of heterodimerization have also been reported. The K2P channel subunits TRESK and TREK-2 provide the predominant background potassium current in the primary sensory neurons of the dorsal root and trigeminal ganglia. A recent study has shown that a TRESK mutation causes migraine because it leads to the formation of a dominant negative truncated TRESK fragment. Surprisingly, this fragment can also interact with TREK-2. In this study, we determined the biophysical and pharmacological properties of the TRESK/TREK-2 heterodimer using a covalently linked TRESK/TREK-2 construct to ensure the assembly of the different subunits. The tandem channel has an intermediate single channel conductance compared to the TRESK and TREK-2 homodimers. Similar conductance values were recorded when TRESK and TREK-2 were coexpressed, demonstrating that the two subunits can spontaneously form functional heterodimers. The TRESK component confers calcineurin-dependent regulation to the heterodimer and gives rise to a pharmacological profile similar to the TRESK homodimer, whereas the presence of the TREK-2 subunit renders the channel sensitive to the selective TREK-2 activator T2A3. In trigeminal primary sensory neurons, we detected single channel activity with biophysical and pharmacological properties similar to the TRESK/TREK-2 tandem, indicating that wild type TRESK and TREK-2 subunits coassemble to form functional heterodimeric channels also in native cells.

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Advances in Neurostimulation for Chronic Pain Disorders.

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The Role of the Cerebellum in Pain Perception: A Brain SPECT Perfusion Study in Patients with Burn Injuries.

Virtual reality (VR) is a promising tool for distraction analgesia. This study aims to compare brain perfusion patterns while patients were undergoing burn wound care in two conditions-VR distraction and control (NoVR).

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In an exploratory randomized, double-blind, placebo-controlled, cross-over study, psychoactive doses of intravenous delta-9-tetrahydrocannabinol fail to produce antinociceptive effects in healthy human volunteers.

Animal studies and anecdotal human reports suggest that cannabinoids have antinociceptive effects. Controlled human studies have produced mixed results.

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Spinal manipulation for the management of cervicogenic headache: a systematic review and meta-analysis.

Spinal manipulative therapy (SMT) is frequently used to manage cervicogenic headache (CGHA). No meta-analysis has investigated the effectiveness of SMT exclusively for CGHA.

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Auditory attention alterations in migraine: A behavioral and MEG/EEG study.

To evaluate alterations of top-down and/or bottom-up attention in migraine and their cortical underpinnings.

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Evaluation of 2-Hour Post-Dose Efficacy of Lasmiditan for the Acute Treatment of Difficult-to-Treat Migraine Attacks.

To identify factors predicting response (2-hour headache pain freedom or most bothersome symptom freedom) to lasmiditan based on individual patient characteristics, migraine disease characteristics, and migraine attack characteristics. Further, efficacy specifically in difficult-to-treat patient/migraine disease characteristics or attack characteristics (ie, historically considered less responsive to certain acute therapies) subgroups was analyzed.

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Chemogenetic Regulation of CX3CR1-Expressing Microglia Using Gi-DREADD Exerts Sex-Dependent Anti-Allodynic Effects in Mouse Models of Neuropathic Pain.

Despite growing evidence suggesting that spinal microglia play an important role in the molecular mechanism underlying experimental neuropathic pain (NP) in male rodents, evidence regarding the sex-dependent role of these microglia in NP is insufficient. In this study, we evaluated the effects of microglial regulation on NP using Gi-designer receptors exclusively activated by designer drugs (Gi-DREADD) driven by the microglia-specific promoter. For the Cre-dependent expression of human Gi-coupled M4 muscarinic receptors (hM4Di) in CX3C chemokine receptor 1-expressing (CX3CR1) cells, R26-LSL-hM4Di-DREADD mice were crossed with CX3CR1-Cre mice. Mouse models of NP were generated by partial sciatic nerve ligation (PSL) and treatment with anti-cancer agent paclitaxel (PTX) or oxaliplatin (OXA), and mechanical allodynia was evaluated using the von Frey test. Immunohistochemistry revealed that hM4Di was specifically expressed on Iba1 microglia, but not on astrocytes or neurons in the spinal dorsal horn of CX3CR1-hM4Di mice. PSL-induced mechanical allodynia was significantly attenuated by systemic (intraperitoneal, i.p.) administration of 10 mg/kg of clozapine N-oxide (CNO), a hM4Di-selective ligand, in male CX3CR1-hM4Di mice. The mechanical threshold in naive CX3CR1-hM4Di mice was not altered by i.p. administration of CNO. Consistently, local (intrathecal, i.t.) administration of CNO (20 nmol) significantly relieved PSL-induced mechanical allodynia in male CX3CR1-hM4Di mice. However, neither i.p. nor i.t. administration of CNO affected PSL-induced mechanical allodynia in female CX3CR1-hM4Di mice. Both i.p. and i.t. administration of CNO relieved PTX-induced mechanical allodynia in male CX3CR1-hM4Di mice, and a limited effect of i.p. CNO was observed in female CX3CR1-hM4Di mice. Unlike PTX-induced allodynia, OXA-induced mechanical allodynia was slightly improved, but not significantly relieved, by i.p. administration of CNO in both male and female CX3CR1-hM4Di mice. These results suggest that spinal microglia can be regulated by Gi-DREADD and support the notion that CX3CR1 spinal microglia play sex-dependent roles in nerve injury-induced NP; however, their roles may vary among different models of NP.

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Cortical Mechanisms of Single-Pulse Transcranial Magnetic Stimulation in Migraine.

Single-pulse transcranial magnetic stimulation (sTMS) of the occipital cortex is an effective migraine treatment. However, its mechanism of action and cortical effects of sTMS in migraine are yet to be elucidated. Using calcium imaging and GCaMP-expressing mice, sTMS did not depolarise neurons and had no effect on vascular tone. Pre-treatment with sTMS, however, significantly affected some characteristics of the cortical spreading depression (CSD) wave, the correlate of migraine aura. sTMS inhibited spontaneous neuronal firing in the visual cortex in a dose-dependent manner and attenuated L-glutamate-evoked firing, but not in the presence of GABA antagonists. In the CSD model, sTMS increased the CSD electrical threshold, but not in the presence of GABA antagonists. We first report here that sTMS at intensities similar to those used in the treatment of migraine, unlike traditional sTMS applied in other neurological fields, does not excite cortical neurons but it reduces spontaneous cortical neuronal activity and suppresses the migraine aura biological substrate, potentially by interacting with GABAergic circuits.

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Immortalized Dorsal Root Ganglion Neuron Cell Lines.

Pain is one of the most significant causes of suffering and disability world-wide, and arguably the most burdensome global health challenge. The growing number of patients suffering from chronic pain conditions such as fibromyalgia, complex regional pain syndrome, migraine and irritable bowel syndrome, not only reflect the complexity and heterogeneity of pain types, but also our lack of understanding of the underlying mechanisms. Sensory neurons within the dorsal root ganglia (DRG) have emerged as viable targets for effective chronic pain therapy. However, DRG's contain different classes of primary sensory neurons including pain-associated nociceptive neurons, non-nociceptive temperature sensing, mechanosensory and chemoreceptive neurons, as well as multiple types of immune and endothelial cells. This cell-population heterogeneity makes investigations of individual subgroups of DRG neurons, such as nociceptors, difficult. In attempts to overcome some of these difficulties, a limited number of immortalized DRG-derived cell lines have been generated over the past few decades. experiments using DRG-derived cell lines have been useful in understanding sensory neuron function. In addition to retaining phenotypic similarities to primary cultured DRG neurons, these cells offer greater suitability for high throughput assays due to ease of culture, maintenance, growth efficiency and cost-effectiveness. For accurate interpretation and translation of results it is critical, however, that phenotypic similarities and differences of DRG-derived cells lines are methodically compared to native neurons. Published reports to date show notable variability in how these DRG-derived cells are maintained and differentiated. Understanding the cellular and molecular differences stemming from different culture methods, is essential to validate past and future experiments, and enable these cells to be used to their full potential. This review describes currently available DRG-derived cell lines, their known sensory and nociceptor specific molecular profiles, and summarize their morphological features related to differentiation and neurite outgrowth.

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Default mode network connectivity is related to pain frequency and intensity in adolescents.

Pain during adolescence is common and is associated with future pain chronicity and mental health in adulthood. However, understanding of the neural underpinnings of chronic pain has largely come from studies in adults, with recent studies in adolescents suggesting potentially unique neural features during this vulnerable developmental period. In addition to alterations in the pain network, resting state functional magnetic resonance imaging studies in adults suggest alterations in the default mode network (DMN), involved in internally-driven, self-referential thought, may underlie chronic pain; however, these findings have yet to be examined in adolescents. The current study sought to investigate associations between pain frequency and intensity, and disruptions in DMN connectivity, in adolescents. Adolescents (ages 12-20) with varying levels of pain frequency and intensity, recruited from a pediatric pain clinic and the local community (n = 86; 60% female), underwent resting state functional magnetic resonance imaging. Using independent components analysis, the DMN was identified and correlated voxel-wise to assess associations between pain frequency and intensity and DMN connectivity. Findings revealed that adolescents with greater pain frequency demonstrated greater DMN to superior frontal gyrus connectivity, while adolescents with greater pain intensity demonstrated lesser DMN to cerebellum (lobule VIII) connectivity, during rest. These findings suggest that increasing levels of pain are associated with potential desegregation of the DMN and the prefrontal cortex, important for cognitive control, and with novel patterns of DMN to cerebellum connectivity. These findings may prove beneficial as neurobiological targets for future treatment efforts in adolescents.

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Acute sleep deprivation enhances susceptibility to the migraine substrate cortical spreading depolarization.

Migraine is a common headache disorder, with cortical spreading depolarization (CSD) considered as the underlying electrophysiological event. CSD is a slowly propagating wave of neuronal and glial depolarization. Sleep disorders are well known risk factors for migraine chronification, and changes in wake-sleep pattern such as sleep deprivation are common migraine triggers. The underlying mechanisms are unknown. As a step towards developing an animal model to study this, we test whether sleep deprivation, a modifiable migraine trigger, enhances CSD susceptibility in rodent models.

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Automated Nociceptive Withdrawal Reflex Measurements Reveal Normal Reflex Thresholds and Augmented Pain Ratings in Patients with Fibromyalgia.

The nociceptive withdrawal reflex (NWR) is used to probe spinal cord excitability in chronic pain states. Here, we used an automated and unbiased procedure for determining the NWR threshold and compared the reflex thresholds and corresponding pain ratings in a well-characterized cohort of fibromyalgia ( = 29) and matched healthy controls ( = 21). Surface electrical stimuli were delivered to the foot in a stepwise incremental and decremental manner. The surface electromyographic activity was recorded from the ipsilateral tibialis anterior muscle. Fibromyalgia patients reported significantly higher scores for psychological distress and pain-related disability and a significantly lower score for perceived state of health compared to the matched controls. The subjective pain ratings were significantly higher in patients. The NWR thresholds were similar to the controls. In the patients, but not in controls, the NWR thresholds and subjective pain ratings were significantly correlated. Our results showed an increased subjective pain sensitivity in fibromyalgia, but we found no evidence for spinal sensitization based on the reflex measures.

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Delta opioid receptor activation modulates affective pain and modality-specific pain hypersensitivity associated with chronic neuropathic pain.

Delta opioid receptor (DOR) agonists alleviate nociceptive behaviors in various chronic pain models, including neuropathic pain, while having minimal effect on sensory thresholds in the absence of injury. The mechanisms underlying nerve injury-induced enhancement of DOR function are unclear. We used a peripheral nerve injury (PNI) model of neuropathic pain to assess changes in the function and localization of DORs in mice and rats. Intrathecal administration of DOR agonists reversed mechanical allodynia and thermal hyperalgesia. The dose-dependent thermal antinociceptive effects of DOR agonists were shifted to the left in PNI rats. Administration of DOR agonists produced a conditioned place preference in PNI, but not in sham, animals, whereas the DOR antagonist naltrindole produced a place aversion in PNI, but not in sham, mice, suggesting the engagement of endogenous DOR activity in suppressing pain associated with the injury. GTPγS autoradiography revealed an increase in DOR function in the dorsal spinal cord, ipsilateral to PNI. Immunogold electron microscopy and in vivo fluorescent agonist assays were used to assess changes in the ultrastructural localization of DORs in the spinal dorsal horn. In shams, DORs were primarily localized within intracellular compartments. PNI significantly increased the cell surface expression of DORs within lamina IV-V dendritic profiles. Using neonatal capsaicin treatment, we identified that DOR agonist-induced thermal antinociception was mediated via receptors expressed on primary afferent sensory neurons but did not alter mechanical thresholds. These data reveal that the regulation of DORs following PNI and suggest the importance of endogenous activation of DORs in regulating chronic pain states.

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Movement, posture and low back pain. How do they relate? A replicated single-case design in 12 people with persistent, disabling low back pain.

Movement and posture are commonly believed to relate to non-specific low back pain (NSLBP). While people with NSLBP appear to move and posture themselves differently from those without NSLBP, changes in movement and posture infrequently relate to improvements in NSLBP when analysed at a group-level. Additionally, little is known about how movement or posture change when clinical outcome improves.

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Serotonin and noradrenaline modulate chronic itch processing in mice.

The roles of serotonin and noradrenaline in the modulation of chronic pruriceptive processing currently remain unclear. To clarify the contribution of serotonin and noradrenaline to chronic itch, the effects of the administration of antidepressants or noradrenaline reuptake inhibitors were evaluated in the present study. A pretreatment with milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, attenuated the induction of spontaneous scratching behavior in mice with chronic itch. The administration of a serotonin reuptake inhibitor, such as fluvoxamine and paroxetine, but not escitalopram, or a noradrenaline reuptake inhibitor, such as atomoxetine and nisoxetine, ameliorated the induction of spontaneous scratching behavior in mice with chronic itch. Furthermore, this attenuation was reversed by the administration of yohimbine, a selective α-adrenoceptor antagonist, or methysergide, a non-selective serotonin receptor antagonist. These results suggest that elevated serotonin and noradrenaline levels are involved in the attenuation of scratching behavior induced by chronic itch, and serotonin receptors and an α-adrenoceptor play a crucial role in chronic pruriceptive processing.

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Predictors of worsening neuropathy and neuropathic pain after 12 years in people with HIV.

Distal sensory polyneuropathy (DSP) and neuropathic pain are important clinical concerns in virally suppressed people with HIV. We determined how these conditions evolved, what factors influenced their evolution, and their clinical impact.

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Neurobiological biomarkers of response to ketamine.

As a field, psychiatry is undergoing an exciting paradigm shift toward early identification and intervention that will likely minimize both the burden associated with severe mental illnesses as well as their duration. In this context, the rapid-acting antidepressant ketamine has revolutionized our understanding of antidepressant response and greatly expanded the pharmacologic armamentarium for treatment-resistant depression. Efforts to characterize biomarkers of ketamine response support a growing emphasis on early identification, which would allow clinicians to identify biologically enriched subgroups with treatment-resistant depression who are more likely to benefit from ketamine therapy. This chapter presents a broad overview of a range of translational biomarkers, including those drawn from imaging and electrophysiological studies, sleep and circadian rhythms, and HPA axis/endocrine function as well as metabolic, immune, (epi)genetic, and neurotrophic biomarkers related to ketamine response. Ketamine's unique, rapid-acting properties may serve as a model to explore a whole new class of novel rapid-acting treatments with the potential to revolutionize drug development and discovery. However, it should be noted that although several of the biomarkers reviewed here provide promising insights into ketamine's mechanism of action, most studies have focused on acute rather than longer-term antidepressant effects and, at present, none of the biomarkers are ready for clinical use.

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Bibliometric Analysis of Exercise and Neuropathic Pain Research.

Neuropathic pain, a type of chronic pain, is difficult to treat clinically. Mounting evidence suggests that exercise can effectively ease neuropathic pain, and the number of publications related to exercise and neuropathic pain has increased over time. However, bibliometrics is rarely used in analyzing the general aspects of studies on exercise and neuropathic pain. The present study aims to provide a systematic overview of global scientific research related to exercise and neuropathic pain from 2005 to 2019.

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Pain Among Cancer Survivors.

Pain is one of the most common symptoms that people with cancer experience. Identification of demographic, physiologic, and behavioral correlates of pain among cancer survivors could help identify subgroups most in need of pain management.

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Differences in resting cerebellar and prefrontal cortical blood flow in spinal cord injury-related neuropathic pain: A brief report.

Little is understood about differences in resting neural activity among those with spinal cord injury (SCI)-related neuropathic pain. The purpose of this pilot study was to determine resting cerebral blood flow differences in persons with SCI-related neuropathic pain compared to healthy, pain-free able-bodied controls. Five persons with paraplegia and ten able-bodied participants were included in this study. Resting blood flow, as measured by a continuous arterial spin labeling (ASL) method of fMRI, was analyzed via statistical parametric mapping. Persons with SCI-related neuropathic pain had significantly lower resting blood flow in the cerebellum (Crus I/II), rostral ventromedial medulla and left insular cortex. In contrast, greater resting blood flow occurred in the medial orbitofrontal cortex among those with SCI-related neuropathic pain compared to controls. Differences in resting blood flow were observed among those with SCI-related pain, particularly in regions that may be involved in affective-motivational and cognitive-evaluative aspects of pain. Larger ASL studies in addition to functional connectivity studies using fMRI are needed to clarify unique neural patterns in this complex and often intractable form of pain.

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PANNEXIN 1 CHANNELS AS A THERAPEUTIC TARGET: STRUCTURE, INHIBITION, AND OUTLOOK.

Pannexin 1 (Panx1) channels are transmembrane proteins that release ATP and play an important role in intercellular communication. They are widely expressed in somatic and nervous system tissues, and their activity has been associated with many pathologies such as stroke, epilepsy, inflammation, and chronic pain. While there are a variety of small molecules known to inhibit Panx1, currently little is known about the mechanism of channel inhibition, and there is a dearth of sufficiently potent and selective drugs targeting Panx1. Herein we provide a review of the current literature on Panx1 structural biology and known pharmacological agents that will help provide a basis for rational development of Panx1 chemical modulators.

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Prospective randomized trial of interventions for vincristine-related neuropathic pain.

To evaluate the efficacy of gabapentin at 20 mg/kg per day in the treatment of vincristine-related neuropathic pain.

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Voltage-dependent modulation of TRPA1 currents by diphenhydramine.

Diphenhydramine (DPH) has been broadly used to treat allergy. When used as a topical medicine, DPH temporarily relieves itching and pain. Although transient receptor potential type A1 (TRPA1) channel is known to play roles in both acute and chronic itch and pain, whether DPH affects the activities of TRPA1 remains unclear. Using whole-cell patch clamp recordings, we demonstrated that DPH modulates the voltage-dependence of TRPA1. When co-applied with a TRPA1 agonist, DPH significantly enhanced the inward currents while suppressing the outward currents of TRPA1, converting the channel from outwardly rectifying to inwardly rectifying. This effect of DPH occurred no matter TRPA1 was activated by an electrophilic or non-electrophilic agonist and for both mouse and human TRPA1. The modulation of TRPA1 by DPH was maintained in the L906C mutant, which by itself also causes inward rectification of TRPA1, indicating that additional acting sites are present for the modulation of TRPA1 currents by DPH. Our recordings also revealed that DPH partially blocked capsaicin evoked TRPV1 currents. These data suggest that DPH may exert its therapeutic effects on itch and pain, through modulation of TRPA1 in a voltage-dependent fashion.

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Atopic dermatitis displays stable and dynamic skin transcriptome signatures.

Skin transcriptome studies in atopic dermatitis (AD) showed broad dysregulation as well as "improvement" under therapy. These observations were mainly made in trials and based on microarray data.

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Guidance on authorship with and acknowledgement of patient partners in patient-oriented research.

The Strategy for Patient-Oriented Research Chronic Pain Network was founded in 2016 and is a patient-oriented research network funded by the Canadian Institutes of Health Research. The Network incorporates patient partners throughout its governance and operations meaning that patient partners may contribute to research projects in ways that warrant scientific authorship as defined by the International Committee of Medical Journal Editors. The Network did a brief informal review of guidance on patient authorship in 2019, but could not find any practical documentation to guide its members on this topic. Note the term patient partner here refers to a patient (or caregiver or other person with lived experience) who is a partner or collaborator on a research team. This guidance does not address patients as participants in a research study. This guidance has been co-written by a group of researchers and patient partners of the Chronic Pain Network in an effort to address this gap. It is intended for both researchers and patient partner audiences. This guidance is meant to facilitate conversations between researchers and patient partners about authorship and/or acknowledgement regarding research projects on which they collaborate. While the overall principles of academic authorship and acknowledgement remain unchanged, nuances for interpreting these principles through the lens of patient engagement or patient-oriented research is provided. Teams that carry out patient-oriented research projects will require different preparation to empower all team members (researchers and patient partners) to discuss authorship and acknowledgement. To facilitate these conversations, we have included an overview of the scientific publishing process, explanation of some common terms, and sets of considerations are provided for both patient partners and researchers in determining the range of team member contribution from acknowledgement to authorship. Conversations about authorship can be difficult, even for established research teams. This guidance, and the resources discussed within it, are provided with the intention of making these conversations easier and more thoughtful.

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Brain-behaviour correlates of habitual motivation in chronic back pain.

Chronic pain may sap the motivation for positive events and stimuli. This may lead to a negative behavioural cycle reducing the establishment of appetitive habitual engagement. One potential mechanism for this might be biased learning. In our experiment, chronic back pain patients and healthy controls completed an appetitive Pavlovian-instrumental transfer procedure. We examined participants` behaviour and brain activity and reported pain, depression and anxiety. Patients showed reduced habitual behaviour and increased responses in the hippocampus than controls. This behavioural bias was related to motivational value and reflected in the updating of brain activity in prefrontal-striatal-limbic circuits. Moreover, this was influenced by pain symptom duration, depression and anxiety (explained variance: up to 50.7%). Together, findings identify brain-behaviour pathways for maladaptive habitual learning and motivation in chronic back pain, which helps explaining why chronic pain can be resistant to change, and where clinical characteristics are significant modulators.

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NLRP12 controls arthritis severity by acting as a checkpoint inhibitor of Th17 cell differentiation.

Nucleotide oligomerization domain (NOD)-like receptor-12 (NLRP12) has emerged as a negative regulator of inflammation. It is well described that the Th17 cell population increases in patients with early Rheumatoid Arthritis (RA), which correlates with the disease activity. Here, we investigated the role of NLRP12 in the differentiation of Th17 cells and the development of experimental arthritis, using the antigen-induced arthritis (AIA) murine model. We found that Nlrp12 mice develop severe arthritis characterized by an exacerbated Th17-mediated inflammatory response with increases in the articular hyperalgesia, knee joint swelling, and neutrophil infiltration. Adoptive transfer of Nlrp12 cells into WT mice recapitulated the hyperinflammatory response seen in Nlrp12 mice and the treatment with anti-IL-17A neutralizing antibody abrogated arthritis development in Nlrp12 mice, suggesting that NLRP12 works as an inhibitor of Th17 cell differentiation. Indeed, Th17 cell differentiation markedly increases in Nlrp12 T cells cultured under the Th17-skewing condition. Mechanistically, we found that NLRP12 negatively regulates IL-6-induced phosphorylation of STAT3 in T cells. Finally, pharmacological inhibition of STAT3 reduced Th17 cell differentiation and abrogated hyperinflammatory arthritis observed in Nlrp12 mice. Thus, we described a novel role for NLRP12 as a checkpoint inhibitor of Th17 cell differentiation, which controls the severity of experimental arthritis.

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Upregulation of miR-133a-3p in the Sciatic Nerve Contributes to Neuropathic Pain Development.

The micro (mi)RNAs expressed in the sciatic nerve of streptozotocin (STZ)-induced diabetic rats were evaluated in terms of their therapeutic potential in patients with diabetic neuropathic pain (DNP). Relative miRNA expression in sciatic nerve with DNP was analyzed using next-generation sequencing and quantitative PCR. Potential downstream targets of miRNAs were predicted using Ingenuity Pathway Analysis and the TargetScan database. In vitro experiments were performed using miR-133a-3p-transfected RSC96 Schwann cells. We performed micro-Western and Western blotting and immunofluorescence analyses to verify the role of miR-133a-3p. In vivo, the association between miR-133a-3p with DNP was analyzed via AAV-miR-133a-3p intraneural (intra-epineural but extrafascicular) injection into the sciatic nerve of normal rats or injection of an miR-133a-3p antagomir into the sciatic nerve of diabetes mellitus (DM) rats. miR-133a-3p mimics transfected into RSC96 Schwann cells increased VEGFR-2, p38α MAPK, TRAF-6, and PIAS3 expression and reduced NFκB p50 and MKP3 expression. In normal rats, AAV-miR-133a-3p delivery via intraneural injection into the sciatic nerve induced mechanical allodynia and p-p38 MAPK activation. In DM rats, miR-133a-3p antagomir administration alleviated DNP and downregulated p-p38 phosphorylation. Overexpression of miR-133a-3p in the sciatic nerve induced such pain. We suggest that miR-133a-3p is a potential therapeutic target for DNP.

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Therapeutic ultrasound for chronic low back pain.

This is an update of a Cochrane Review published in 2014. Chronic non-specific low back pain (LBP) has become one of the main causes of disability in the adult population around the world. Although therapeutic ultrasound is not recommended in recent clinical guidelines, it is frequently used by physiotherapists in the treatment of chronic LBP.

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Examining emotional pain among individuals with chronic physical pain: Nomothetic and idiographic approaches.

Emotional pain (i.e., pain affect in response to psychological experiences such as rejection or loss) may be a component of chronic pain syndromes given high co-occurrence with depression and neurobiological overlaps in pain affect resulting from physical and emotional experiences. In the current set of studies, we examined the relationship between emotional and physical pain using both nomothetic (i.e., group-level) and idiographic (i.e., individual-level) approaches.

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New insights into the mechanisms behind mechanical itch.

Gentle tactile stimuli, such as insects crawling on the skin, can cause itching sensation called mechanical itch. Recent studies have begun to shed light on the neural mechanisms of mechanical itch. Interestingly, the neural pathway for mechanical itch is apparently different from that for chemical itch triggered by the activation of pruriceptors with various mediators. Mechanical itch dysesthesia is frequently seen in patients with chronic itch. Mechanisms of this dysesthesia are plausibly involved in central sensitization. In this review, we summarize the current knowledge of mechanical itch under normal and pathological conditions.

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Improvement of Pain and Function After Use of a Topical Pain Relieving Patch: Results of the RELIEF Study.

Pain is the most common reason for patients to consult primary care providers. Identification of effective treatments with minimal adverse events is critical to safer opioid-sparing and multi-modal approaches to pain treatment. Topical analgesic patches target medication to peripheral sites of pain while potentially avoiding adverse effects associated with systemic medications. Opioids, prescription nonsteroidal anti-inflammatory drugs, and over-the-counter oral medications are associated with systemic toxicities, increasing morbidity and mortality. This study evaluated a topical analgesic pain-relieving patch in reducing pain severity and improving function in patients with mild to moderate arthritic, neurological, or musculoskeletal pain.

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P2X7 receptors exert a permissive effect on the activation of presynaptic AMPA receptors in rat trigeminal caudal nucleus glutamatergic nerve terminals.

Purine receptors play roles in peripheral and central sensitization and are associated with migraine headache. We investigated the possibility that ATP plays a permissive role in the activation of AMPA receptors thus inducing Glu release from nerve terminals isolated from the rat trigeminal caudal nucleus (TCN).

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Pharmacological Characterization of a Novel Mouse Model of Cholestatic Pruritus.

Patients with cholestatic liver diseases, such as primary biliary cirrhosis, usually suffer from pruritus. However, the pathogenesis of cholestatic pruritus is unclear, and there is no current effective treatment for it. In order to find a treatment for the condition, an appropriate mouse model should be developed. Therefore, here, we established a surgically-induced mouse model of cholestatic pruritus. The bile duct was ligated in order to block bile secretion from the anterior, right, and left lobes, with the exception of the caudate lobe. Serum levels of total bile acid increased after bile duct ligation (BDL). The spontaneous hind paw scratching was also increased in BDL mice. Spontaneous scratching was reduced in BDL mice by naloxone (µ-opioid receptor antagonist), U-50,488H (κ-opioid receptor agonist), and clonidine (α2-adrenoceptor agonist). Azelastine (H receptor antagonist with membrane-stabilizing activity) slightly reduced scratching. However, terfenadine (H receptor antagonist), methysergide (serotonin (5-HT) receptor antagonist), ondansetron (5-HT receptor antagonist), proteinase-activated receptor 2-neutralizing antibody, fluvoxamine (selective serotonin reuptake inhibitor), milnacipran (serotonin-noradrenalin reuptake inhibitor), and cyproheptadine (H and 5-HT receptor antagonist) did not affect scratching. These results suggested that partial obstruction of bile secretion in mice induced anti-histamine-resistant itching and that central opioid system is involved in cholestatic itching.

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Influence of self-reported physical activity and sleep quality on conditioned pain modulation in the orofacial region.

To evaluate the influence of self-reported physical activity and sleep quality on conditioned pain modulation (CPM) in the orofacial region.

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Impact of neuropathic pain on participation: perspectives from the Canadian SCI community survey.

Secondary analysis of an observational cohort study.

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Gene expression of endocannabinoid system in HIV-1-related neuropathic pain model.

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Neuroimaging findings in headache with normal neurologic examination: Systematic review and meta-analysis.

To determine if pooled estimates of the prevalence of unexpected findings in patients with headache and normal neurologic examination support current expert opinion-based neuroimaging guidelines.

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The association between exposure to childhood maltreatment and the subsequent development of functional somatic and visceral pain syndromes.

Childhood maltreatment is a global public health issue linked to a vast mortality and morbidity burden. This study builds on current literature to explore the risk of developing central sensitivity syndromes (CSS) (consisting of somatic and visceral pain syndromes) subsequent to childhood maltreatment exposure.

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Machine learning approach to predict medication overuse in migraine patients.

Machine learning (ML) is largely used to develop automatic predictors in migraine classification but automatic predictors for medication overuse (MO) in migraine are still in their infancy. Thus, to understand the benefits of ML in MO prediction, we explored an automated predictor to estimate MO risk in migraine. To achieve this objective, a study was designed to analyze the performance of a customized ML-based decision support system that combines support vector machines and Random Optimization (RO-MO). We used RO-MO to extract prognostic information from demographic, clinical and biochemical data. Using a dataset of 777 consecutive migraine patients we derived a set of predictors with discriminatory power for MO higher than that observed for baseline SVM. The best four were incorporated into the final RO-MO decision support system and risk evaluation on a five-level stratification was performed. ROC analysis resulted in a c-statistic of 0.83 with a sensitivity and specificity of 0.69 and 0.87, respectively, and an accuracy of 0.87 when MO was predicted by at least three RO-MO models. Logistic regression analysis confirmed that the derived RO-MO system could effectively predict MO with ORs of 5.7 and 21.0 for patients classified as probably (3 predictors positive), or definitely at risk of MO (4 predictors positive), respectively. In conclusion, a combination of ML and RO – taking into consideration clinical/biochemical features, drug exposure and lifestyle – might represent a valuable approach to MO prediction in migraine and holds the potential for improving model precision through weighting the relative importance of attributes.

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Interactions Among lncRNAs/circRNAs, miRNAs, and mRNAs in Neuropathic Pain.

Neuropathic pain (NP) is directly caused by an injury or disease of the somatosensory nervous system. It is a serious type of chronic pain that is a burden to the economy and public health. Although recent studies have improved our understanding of NP, its pathogenesis has not been fully elucidated. Noncoding RNAs, including lncRNAs, circRNAs, and miRNAs, are involved in the pathological development of NP through many mechanisms. In addition, extensive evidence suggests that novel regulatory mechanisms among lncRNAs/circRNAs, miRNAs, and mRNAs play a crucial role in the pathophysiological process of NP. In this review, we comprehensively summarize the regulatory relationship among lncRNAs/circRNAs, miRNAs, and mRNAs and emphasize the important role of the lncRNA/circRNA-miRNA-mRNA axis in NP.

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Examining the Effects of (α4)3(β2)2 Nicotinic Acetylcholine Receptor-Selective Positive Allosteric Modulator on Acute Thermal Nociception in Rats.

Neuronal nicotinic acetylcholine receptor (nAChR)-based therapeutics are sought as a potential alternative strategy to opioids for pain management. In this study, we examine the antinociceptive effects of 3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1-pyrazol-4-yl)isoxazole (CMPI), a novel positive allosteric modulator (PAM), with preferential selectivity to the low agonist sensitivity (α4)3(β2)2 nAChR and desformylflustrabromine (dFBr), a PAM for α4-containing nAChRs. We used hot plate and tail flick tests to measure the effect of dFBr and CMPI on the latency to acute thermal nociceptive responses in rats. Intraperitoneal injection of dFBr, but not CMPI, dose-dependently increased latency in the hot plate test. In the tail flick test, the effect achieved at the highest dFBr or CMPI dose tested was only <20% of the maximum possible effects reported for nicotine and other nicotinic agonists. Moreover, the coadministration of dFBr did not enhance the antinociceptive effect of a low dose of nicotine. Our results show that the direct acute effect of dFBr is superior to that for CMPI, indicating that selectivity to (α4)3(β2)2 nAChR is not advantageous in alleviating responses to acute thermal nociceptive stimulus. However, further studies are necessary to test the suitability of (α4)3(β2)2 nAChR-selective PAMs in chronic pain models.

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The role of methadone in cancer-induced bone pain: a retrospective cohort study.

Cancer-induced bone pain (CIBP) can be challenging to manage in advanced cancer. The unique properties of methadone may have a role in refractory CIBP. We aimed to evaluate the analgesic effects of methadone for CIBP when other opioids are ineffective or intolerable.

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Molecular Dynamics Simulations to Investigate How PZM21 Affects the Conformational State of the μ-Opioid Receptor Upon Activation.

Opioid analgesics such as morphine have indispensable roles in analgesia. However, morphine use can elicit side effects such as respiratory depression and constipation. It has been reported that G protein-biased agonists as substitutes for classic opioid agonists can alleviate (or even eliminate) these side effects. The compounds PZM21 and TRV130 could be such alternatives. Nevertheless, there are controversies regarding the efficacy and G protein-biased ability of PZM21. To demonstrate a rationale for the reduced biasing agonism of PZM21 compared with that of TRV130 at the molecular level, we undertook a long-term molecular dynamics simulation of the μ-opioid receptor (MOR) upon the binding of three ligands: morphine, TRV130, and PZM21. We found that the delayed movement of the W293 (Ballesteros-Weinstein numbering) side chain was a factor determining the dose-dependent agonism of PZM21. Differences in conformational changes of W318, Y326, and Y336 in PZM21 and TRV130 explained the observed differences in bias between these ligands. The extent of water movements across the receptor channel was correlated with analgesic effects. Taken together, these data suggest that the observed differences in conformational changes of the studied MOR-ligand complexes point to the low-potency and lower bias effects of PZM21 compared with the other two ligands, and they lay the foundation for the development of G protein-biased agonists.

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MicroRNA-330 Directs Downregulation of the GABAR2 in the Pathogenesis of Pancreatic Cancer Pain.

Pancreatic cancer is one of the most aggressive and deadly malignancies with a very poor prognosis. Pancreatic cancer-induced visceral pain is very common and is generally presented among the initial symptoms in patients; such pain is strongly associated with poor quality of life, impaired functional activity, and decreased survival. However, the principal neurobiological mechanisms of pain caused by pancreatic cancer have not been fully elucidated. Accumulating studies have shown that miRNAs play a major role in chronic pain by suppressing key molecules involved in nociception. In the present study, we report that microRNA (miR)-330 is highly expressed in the spinal dorsal horn (SDH) of nude mice with pancreatic cancer pain. Mimicking pancreatic carcinoma-induced SDH miR-330 upregulation by microinjection of miR-330 mimic into the SDH significantly induced abdominal mechanical allodynia in normal nude mice. Additionally, we found that the expression of GABAR2 was significantly decreased in the SDH of nude mice with pancreatic cancer pain and was regulated directly by miR-330 both in vitro and in vivo. Furthermore, inhibition of miR-330 rescued the expression of GABAR2 and alleviated pancreatic carcinoma-induced abdominal pain hypersensitivity in nude mice with pancreatic carcinoma. These results show that miR-330 participates in the genesis of pancreatic carcinoma-induced pain hypersensitivity by inhibiting GABAR2 expression in the SDH and might be a potential therapeutic target for pancreatic cancer pain.

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Indirect effect of sleep on abdominal pain through daytime dysfunction in adults with irritable bowel syndrome.

Sleep deficiency, psychological distress, daytime dysfunction and abdominal pain are common in adults with irritable bowel syndrome (IBS). Prior research on individuals with chronic pain has identified the indirect effect of sleep on pain through psychological distress or daytime dysfunction; however, it is less clear in IBS. The purpose of this study was to examine potential indirect effects of sleep on abdominal pain symptoms simultaneously through psychological distress and daytime dysfunction in adults with IBS.

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Erenumab in highly therapy-refractory migraine patients: First German real-world evidence.

Calcitonin gene related peptide (CGRP) monoclonal antibodies (mAB) are the first specific migraine prophylactic medication. Erenumab is the only CGRP mAB targeting the CGRP receptor. Clinical data regarding efficacy and tolerability of erenumab in highly therapy-refractory patients are not available, yet, although many patients treated with CGRP mAB under real world conditions can be considered as highly therapy-refractory.

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Serum Homocysteine, Pyridoxine, Folate, and Vitamin B12 Levels in Migraine: Systematic Review and Meta-Analysis.

Migraine, especially migraine with aura (MA), has been linked to increased risk for ischemic cerebrovascular disease. The possible role of elevated serum homocysteine (Hcy, a cause of thrombophilia) in migraine has been demonstrated by several studies.

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Chronic Pain, Mood Disorders and Substance Use: Outcomes of Interdisciplinary Care in a Residential Psychiatric Hospital.

The objective is to report outcomes of an interdisciplinary group-based residential chronic pain recovery program (CPRC), located in a private non-profit psychiatric hospital. The chronic pain program was aimed at treatment and engagement in self-care of both pain and co-occurring disorders in a residential facility that also offered treatment for specific psychiatric disorders.

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