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Papers: 17 Oct 2020 - 23 Oct 2020

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Delivering transformative action in paediatric pain: a Lancet Child & Adolescent Health Commission.

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Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia.

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated mutation (p.Cys188Trp) in the GABA receptor Cl channel γ-1 subunit () exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na and Ca channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca channel Ca3.2 (). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

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Functional α6β4 acetylcholine receptor expression enables pharmacological testing of nicotinic agonists with analgesic properties.

The α6β4 nicotinic acetylcholine receptor (nAChR) is enriched in dorsal root ganglia neurons and is an attractive non-opioid therapeutic target for pain. However, difficulty expressing human α6β4 receptors in recombinant systems has precluded drug discovery. Here, genome-wide screening identified accessory proteins that enable reconstitution of human α6β4 nAChRs. BARP, an auxiliary subunit of voltage-dependent calcium channels, promoted α6β4 surface expression while IRE1α, an unfolded protein response sensor, enhanced α6β4 receptor assembly. Effects on α6β4 involve BARP's N-terminal region and IRE1α's splicing of XBP1 mRNA. Furthermore, clinical efficacy of nicotinic agents in relieving neuropathic pain best correlated with their activity on α6β4. Finally, BARP-knockout, but not NACHO-knockout mice lacked nicotine-induced antiallodynia, highlighting the functional importance of α6β4 in pain. These results identify roles for IRE1α and BARP in neurotransmitter receptor assembly and unlock drug discovery for the previously elusive α6β4 receptor.

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An Open Resource for Non-human Primate Optogenetics.

Optogenetics has revolutionized neuroscience in small laboratory animals, but its effect on animal models more closely related to humans, such as non-human primates (NHPs), has been mixed. To make evidence-based decisions in primate optogenetics, the scientific community would benefit from a centralized database listing all attempts, successful and unsuccessful, of using optogenetics in the primate brain. We contacted members of the community to ask for their contributions to an open science initiative. As of this writing, 45 laboratories around the world contributed more than 1,000 injection experiments, including precise details regarding their methods and outcomes. Of those entries, more than half had not been published. The resource is free for everyone to consult and contribute to on the Open Science Framework website. Here we review some of the insights from this initial release of the database and discuss methodological considerations to improve the success of optogenetic experiments in NHPs.

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Improving Study Conduct and Data Quality in Clinical Trials of Chronic Pain Treatments: IMMPACT Recommendations.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.

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The antinociceptive properties of an isoform-selective inhibitor of Nav1.7 derived from saxitoxin in mouse models of pain.

The voltage gated sodium channel Nav1.7 is highly expressed in nociceptive afferents and is critically involved in pain signal transmission. Nav1.7 is a genetically validated pain target in humans, as loss-of-function mutations cause congenital insensitivity to pain, and gain-of-function mutations cause severe pain syndromes. Consequently pharmacological inhibition has been investigated as an analgesic therapeutic strategy. We describe a small molecule Nav1.7 inhibitor, ST-2530, that is an analog of the naturally occurring sodium channel blocker saxitoxin. When evaluated against human Nav1.7 by patch clamp electrophysiology using a protocol that favors the resting state, the Kd of ST-2530 was 25 ± 7 nM. ST-2530 exhibited greater than 500-fold selectivity over human voltage gated sodium channel isoforms Nav1.1-Nav1.6 and Nav1.8. While ST-2530 had lower affinity against mouse Nav1.7 (Kd = 250 ± 40 nM), potency was sufficient to assess analgesic efficacy in mouse pain models. A 3 mg/kg dose administered subcutaneously was broadly analgesic in acute pain models employing noxious thermal, mechanical, and chemical stimuli. ST-2530 also reversed thermal hypersensitivity following a surgical incision on the plantar surface of the hind paw. In the spared nerve injury model of neuropathic pain, ST-2530 transiently reversed mechanical allodynia. These analgesic effects were demonstrated at doses that did not affect locomotion, motor coordination or olfaction. Collectively, results from the present study indicate that pharmacological inhibition of Nav1.7 by a small molecule agent with affinity for the resting state of the channel is sufficient to produce analgesia in a range of preclinical pain models.

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Neuropathic pain therapy: a puzzle of different approaches to stratify patients.

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Trauma-focused cognitive behavioural therapy and exercise for chronic whiplash with comorbid posttraumatic stress disorder: a randomised controlled trial.

Many people with chronic whiplash associated disorders (WAD) also have symptoms of posttraumatic stress disorder (PTSD), but this is rarely considered in usual predominantly exercise based interventions. We aimed to investigate the effectiveness of combined trauma focused cognitive behavioural therapy (TF-CBT) and exercise compared to supportive therapy (ST) and exercise for people with chronic WAD and PTSD. A randomised controlled multi-centre trial with concealed allocation, assessor blinding, and blinded analysis was conducted. 103 participants with chronic WAD (>3 months and <5 years, grade II) and PTSD were randomised to TF-CBT and exercise (n=53) or ST and exercise (n=50). Both interventions comprised 10 weeks of TF-CBT or ST followed by 6 weeks of exercise. Outcomes were measured at baseline, 10 weeks, 16 weeks, 6 months, and 12 months post-randomisation. Analysis was intention to treat using linear mixed models. There was no difference between the interventions on the primary outcome of neck pain related disability at any time point. At 16 weeks, the treatment effect on the 0-100 Neck Disability Index was 0.59 (95% CI 5.51 to -4.33), at 6 months 1.18 (6.15 to -3.78), and at 12 months 1.85 (6.81 to -3.11). In addition, there was no difference between the interventions for the majority of secondary outcomes at any time. Exceptions were in favour of TF-CBT and exercise, where improvements in PTSD symptoms were found at 16 weeks. From 16 weeks onwards, both groups achieved a clinically important improvement in neck pain related disability. However, both groups remained moderately disabled.

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Photophobia in complex regional pain syndrome: visual discomfort is greater on the affected than unaffected side.

In complex regional pain syndrome (CRPS), hyperalgesia encompasses uninjured sites on the ipsilateral side of the body and may also include the special senses, as auditory discomfort often is greater on the CRPS-affected side. To determine whether this hemi-lateral hyperalgesia involves the visual system, the discomfort threshold to a light-source that increased in intensity at 100 lux/second from 500 to 3,600 lux was investigated for each eye, and the nasal and temporal half of each visual field, in 33 patients with CRPS and 21 pain-free controls. Recent headache history was reviewed and, in patients with CRPS, sensitivity to mechanical and thermal stimuli was assessed in all four limbs and on each side of the forehead. In addition, the pupils were photographed in dim and bright light. The visual discomfort threshold was lower in patients than controls and was lower on the CRPS-affected than unaffected side (p < .001), indicating photophobia. Visual discomfort was unrelated to pupil diameter. Headache frequency was greater in CRPS patients than controls, and unilateral headaches were more likely to be on the CRPS-affected than contralateral side. Similarly, mechanical and thermal hyperalgesia was greater in the CRPS-affected than contralateral limb and was greater ipsilateral than contralateral to CRPS in the forehead and non-symptomatic limbs. Ipsilateral photophobia was associated with mechanical and thermal hyperalgesia in the ipsilateral forehead but not the CRPS-affected limb. Together, these findings suggest that aberrant processing of nociceptive input in the ipsilateral trigeminal-medullary region of the brainstem contributes to visual discomfort in CRPS.

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PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia.

The immune checkpoint inhibitor programmed cell death protein 1 (PD-1) plays a critical role in immune regulation. Recent studies have demonstrated functional PD-1 expression in peripheral sensory neurons, which contributes to neuronal excitability, pain, and opioid analgesia. Here we report neuronal expression and function of PD-1 in the central nervous system (CNS), including the spinal cord, thalamus, and cerebral cortex. Notably, GABA-induced currents in spinal dorsal horn neurons, thalamic neurons, and cortical neurons are suppressed by the PD-1-neutralizing immunotherapeutic Nivolumab in spinal cord slices, brain slices, and dissociated cortical neurons. Reductions in GABA-mediated currents in CNS neurons were also observed in P mice without changes in GABA receptor expression. Mechanistically, Nivolumab binds spinal cord neurons and elicits ERK phosphorylation to suppress GABA currents. Finally, both GABA-mediated analgesia and anesthesia are impaired by Pd1 deficiency. Our findings reveal PD-1 as a CNS-neuronal inhibitor that regulates GABAergic signaling and GABA-mediated behaviors.

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Dissimilarity of functional connectivity uncovers the influence of participant’s motion in functional magnetic resonance imaging studies.

Head motion is a major confounding factor impairing the quality of functional magnetic resonance imaging (fMRI) data. In particular, head motion can reduce analytical efficiency, and its effects are still present even after preprocessing. To examine the validity of motion removal and to evaluate the remaining effects of motion on the quality of the preprocessed fMRI data, a new metric of group quality control (QC), dissimilarity of functional connectivity, is introduced. Here, we investigate the association between head motion, represented by mean framewise displacement, and dissimilarity of functional connectivity by applying four preprocessing methods in two independent resting-state fMRI datasets: one consisting of healthy participants (N = 167) scanned in a 3T GE-Discovery 750 with longer TR (2.5 s), and the other of chronic back pain patients (N = 143) in a 3T Siemens Magnetom Prisma scanner with shorter TR (0.555 s). We found that dissimilarity of functional connectivity uncovers the influence of participant's motion, and this relationship is independent of population, scanner, and preprocessing method. The association between motion and dissimilarity of functional connectivity, and how the removal of high-motion participants affects this association, is a new strategy for group-level QC following preprocessing.

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Proteins for increased surface expression of the α6β4 nicotinic acetylcholine receptor: Nothing but good news?

Useful animal models of disease in neuroscience can make accurate predictions about a therapeutic outcome, a feature known as predictive validity. In this issue of the JCI, Knowland et al. provide an improved model to assess nicotinic acetylcholine receptor (nAChR) ligands for treating chronic pain. The authors identify two proteins, the voltage-dependent calcium channel auxiliary subunit BARP and the unfolded protein response sensor IRE1α, that are required for robust heterologous expression of α6β4, an nAChR subtype in dorsal root ganglia (DRG). This nAChR is a candidate for the analgesic effects of nicotine as well as the frog toxin epibatidine. Now researchers can efficiently screen for α6β4 nAChR-selective agonists using heterologous expression systems. Candidates that emerge will enable researchers to test the predictive validity of mouse models for chronic pain in the nAChR context. If all these steps work, one can envision a class of non-opioid nAChR-targeted analgesics for chronic pain.

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Pain prevention and management must begin in childhood: the key role of psychological interventions.

Pain conditions in childhood often continue into adulthood. Childhood chronic pain is related to a range of vulnerabilities that may have contributed to the onset of childhood pain or that may co-occur as a consequence of childhood pain. These vulnerabilities have been shown to maintain pain and disability during childhood but may also contribute to long-term developmental and health impairments that affect adult life. If progress is to be made in reducing the impact of pain and disability through the lifespan, greater efforts need to be directed toward understanding why, for whom, and how pain occurring in childhood affects subsequent adult pain and health. In this review, a developmental framework is applied to link childhood pain to adult pain highlighting childhood vulnerabilities (emotional, health behavior, social/family, and neurobiological) that may represent pathways for interventions in childhood to interrupt this trajectory. Psychological interventions can play a key role in addressing childhood pain and vulnerabilities associated with risk for maladaptive adult outcomes. The review summarizes the evidence base for the effectiveness of psychological interventions for childhood chronic pain and identifies gaps and opportunities to further develop and test early targeted interventions in childhood to reduce childhood chronic pain as well as build resiliency to promote positive adult outcomes. A future research agenda is delineated including the need for longitudinal cohort studies from childhood into adulthood and testing of both targeted early intervention to reduce risk and build resiliency to enhance long-term adult pain, health, developmental, and social outcomes.

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Exploring the activation pathway and G-coupling specificity of the μ-opioid receptor.

Understanding the activation mechanism of the μ-opioid receptor (μ-OR) and its selective coupling to the inhibitory G protein (G) is vital for pharmaceutical research aimed at finding treatments for the opioid overdose crisis. Many attempts have been made to understand the mechanism of the μ-OR activation, following the elucidation of new crystal structures such as the antagonist- and agonist-bound μ-OR. However, the focus has not been placed on the underlying energetics and specificity of the activation process. An energy-based picture would not only help to explain this coupling but also help to explore why other possible options are not common. For example, one would like to understand why μ-OR is more selective to G than a stimulatory G protein (G). Our study used homology modeling and a coarse-grained model to generate all of the possible "end states" of the thermodynamic cycle of the activation of μ-OR. The end points were further used to generate reasonable intermediate structures of the receptor and the G to calculate two-dimensional free energy landscapes. The results of the landscape calculations helped to propose a plausible sequence of conformational changes in the μ-OR and G system and for exploring the path that leads to its activation. Furthermore, in silico alanine scanning calculations of the last 21 residues of the C terminals of G and G were performed to shed light on the selective binding of G to μ-OR. Overall, the present work appears to demonstrate the potential of multiscale modeling in exploring the action of G protein-coupled receptors.

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Greater Conditioned Pain Modulation Is Associated With Enhanced Morphine Analgesia in Healthy Individuals and Patients with Chronic Low Back Pain.

Conditioned pain modulation (CPM) protocols index magnitude of descending pain inhibition. This study evaluated whether degree of CPM, controlling for CPM expectancy confounds, was associated with analgesic and subjective responses to morphine, and whether chronic pain status or sex moderated these effects.

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Dietary Interventions for Treatment of Chronic Pain: Oxidative Stress and Inflammation.

Chronic pain is highly prevalent in the United States, impacting 28.4% of the adult population, or 69.6 million people, as of 2016. Chronic pain is often associated with anxiety, depression, and restrictions in mobility and daily activities, substantially reducing quality of life. Analgesics, especially opioids, are one of the primary pharmaceutical treatment methods for chronic pain. However, prescription opioid misuse and abuse has become increasingly prevalent and concerning, prompting the need for research into alternative treatment methods which avoid the side effects of traditional treatments. Chronic pain is, in part, thought to be the result of oxidative stress and inflammation, and clinical research has indicated links between these conditions and diet. Thus, dietary interventions are a particularly promising therapeutic treatment for chronic pain, with numerous studies suggesting that diet has a noticeable effect on pain as far down as the cellular level. In this review article, data from a number of clinical trials assessing the effect of three diets-antioxidant-rich, low-carbohydrate, and Mediterranean-on oxidative stress and inflammation is compiled and discussed in the context of chronic pain. Clinical data suggests that low-carbohydrate diets and Mediterranean diets both are especially promising dietary interventions.

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‘Reinventing the wheel’ to advance the development of pain therapeutics.

Chronic pain affects approximately one-third of the population worldwide. The primary goal of animal research is to understand the neural mechanisms underlying pain so better treatments can be developed. Despite an enormous investment in time and money, almost no novel treatments for pain have been developed. There are many factors that contribute to this lack of translation in drug development. The mismatch between the goals of drug development in animals (inhibition of pain-evoked responses) and treatment in humans (restoration of function) is a major problem. To solve this problem, a number of pain-depressed behavioral tests have been developed to assess changes in normal behavior in laboratory animals. The use of home cage wheel running as a pain assessment tool is especially useful in that it is easy to use, provides an objective measurement of the magnitude and duration of pain, and is a clinically relevant method to screen novel drugs. Pain depresses activity in humans and animals, and effective analgesic treatments restore activity. Unlike traditional pain-evoked tests (e.g., hot plate, tail flick, von Frey test), restoration of home cage wheel running evaluates treatments for both antinociceptive efficacy and the absence of disruptive side effects (e.g., sedation, paralysis, nausea). This article reviews the literature using wheel running to assess pain and makes the case for home cage wheel running as an effective and clinically relevant method to screen novel analgesics for therapeutic potential.

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Pain Intensity as a Lagging Indicator of Patient Improvement: Longitudinal Relationships with Sleep, Psychiatric Distress, and Function in Multidisciplinary Care.

Despite a common assumption that reductions in chronic pain intensity must precede improvements in other pain-relevant domains, there has been limited empirical inquiry into the temporal ordering of improvements in chronic pain treatment. Cross-lagged models using retrospective clinical data examined relationships between average pain intensity and symptoms of psychological distress, difficulties with sleep initiation and maintenance, and disability in 666 treatment-seeking patients with chronic pain who demonstrated improvement in pain intensity (≥ 1-point reduction on 0-10 numeric rating scale) over a 1-year span. Results indicated that decreased difficulties with sleep initiation, depressive and anxious symptoms, and disability predicted later improvement in pain intensity, whereas greater pain intensity predicted only later difficulties in sleep initiation and maintenance. A combined lagged model highlighted fewer baseline symptoms of PTSD and lower levels of baseline disability as significant predictors of later improvements in pain. Overall, our results indicate that reductions in pain intensity may not be the first factors to change in effective chronic pain management. The current findings should be replicated using prospective studies utilizing structured approaches to maximize data capture, as well as uniform interventional approaches to permit greater inferences regarding causal and temporal aspects of the model. Perspective: This study demonstrates that pain intensity scores are not robust predictors of psychosocial outcomes longitudinally. Instead, other factors such as sleep initiation, psychological distress and disability appear to be important targets for intervention that may promote effective pain reduction.

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Enrichment of genomic pathways based on differential DNA methylation profiles associated with chronic musculoskeletal pain in older adults: An exploratory study.

Our study aimed to identify differentially methylated CpGs/regions and their enriched genomic pathways associated with underlying chronic musculoskeletal pain in older individuals. We recruited cognitively healthy older adults with ( = 20) and without ( = 9) self-reported musculoskeletal pain and collected DNA from peripheral blood that was analyzed using MethylationEPIC arrays. We identified 31,739 hypermethylated CpG and 10,811 hypomethylated CpG probes (s ≤ 0.05). All CpG probes were clustered into 5966 regions, among which 600 regions were differentially methylated at ≤ 0.05 level, including 294 hypermethylated regions and 306 hypomethylated regions (differentially methylated regions). Ingenuity pathway enrichment analysis revealed that the pain-related differentially methylated regions were enriched across multiple pathways. The top 10 canonical pathways were linked to cellular signaling processes related to immune responses (i.e. antigen presentation, programed cell death 1 receptor/PD-1 ligand 1, interleukin-4, OX40 signaling, T cell exhaustion, and apoptosis) and gamma-aminobutyric acid receptor signaling. Further, Weighted Gene Correlation Network Analysis revealed a comethylation network module in the pain group that was not preserved in the control group, where the hub gene was the cyclic adenosine monophosphate-dependent transcription factor ATF-2. Our preliminary findings provide new epigenetic insights into the role of aberrant immune signaling in musculoskeletal pain in older adults while further supporting involvement of dysfunctional GABAergic signaling mechanisms in chronic pain. Our findings need to be urgently replicated in larger cohorts as they may serve as a basis for developing and targeting future interventions.

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Exercise-induced hypoalgesia after acute and regular exercise: experimental and clinical manifestations and possible mechanisms in individuals with and without pain.

Exercise and physical activity is recommended treatment for a wide range of chronic pain conditions. In addition to several well-documented effects on physical and mental health, 8 to 12 weeks of exercise therapy can induce clinically relevant reductions in pain. However, exercise can also induce hypoalgesia after as little as 1 session, which is commonly referred to as exercise-induced hypoalgesia (EIH). In this review, we give a brief introduction to the methodology used in the assessment of EIH in humans followed by an overview of the findings from previous experimental studies investigating the pain response after acute and regular exercise in pain-free individuals and in individuals with different chronic pain conditions. Finally, we discuss potential mechanisms underlying the change in pain after exercise in pain-free individuals and in individuals with different chronic pain conditions, and how this may have implications for clinical exercise prescription as well as for future studies on EIH.

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Median nerve stimulation as a non-pharmacological approach to bypass analgesic tolerance to morphine: a proof-of-concept study in mice.

Analgesic tolerance to opioids contributes to the opioid crisis by increasing the quantity of opioids prescribed and consumed. Thus, there is a need to develop non-opioid-based pain-relieving regimens as well as strategies to circumvent opioid tolerance. Previously, we revealed a non-opioid analgesic mechanism induced by median nerve electrostimulation at the overlaying PC6 (Neiguan) acupoint (MNS-PC6). Here, we further examined the efficacy of MNS-PC6 in morphine-tolerant mice with neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Daily treatments of MNS-PC6 (2 Hz, 2 mA), but not electrostimulation at a non-median nerve-innervated location, for a week post-CCI induction significantly suppressed established mechanical allodynia in CCI-mice in an orexin-1 (OX) and cannabinoid-1 (CB) receptor-dependent fashion. This anti-allodynic effect induced by repeated MNS-PC6 was comparable to that induced by repeated gabapentin (50 mg/kg, i.p.) or single morphine (10 mg/kg, i.p.) treatments, but without tolerance, unlike repeated morphine-induced analgesia. Furthermore, single and repeated MNS-PC6 treatments remained fully effective in morphine-tolerant CCI-mice, also in an OX and CB receptor-dependent fashion. In CCI-mice receiving escalating doses of morphine for 21 days (10 mg/kg, 20 mg/kg and 50 mg/kg), single and repeated MNS-PC6 treatments remained fully effective. Therefore, repeated MNS-PC6 treatments induce analgesia without tolerance, and retain efficacy in opioid-tolerant mice via a mechanism that involves OX and CB receptors. This study suggests that MNS-PC6 is an alternative pain management strategy that maybe useful for combatting the opioid epidemic, and opioid-tolerant patients receiving palliative care. PERSPECTIVES: Median nerve stimulation relieves neuropathic pain in mice without tolerance and retains efficacy even in mice with analgesic tolerance to escalating doses of morphine, via an opioid-independent, orexin-endocannabinoid-mediated mechanism. This study provides a proof of concept for utilizing peripheral nerve stimulating devices for pain management in opioid-tolerant patients.

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Association between migraine and cryptogenic ischemic stroke in young adults.

To assess the association between migraine and cryptogenic ischemic stroke (CIS) in young adults, with subgroup analyses stratified by sex and presence of patent foramen ovale (PFO).

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A Three-Way Crossover Study of Pregabalin, Placebo and the Histamine 3 Receptor Inverse Agonist AZD5213 in Combination with Pregabalin in Subjects with Painful Diabetic Neuropathy and Good Pain-Reporting Ability.

In this study, patients with painful diabetic neuropathy (PDN) were trained using an experimental pain paradigm in an attempt to enroll a subset of patients who are "pain connoisseurs" and therefore more able to discriminate between active and placebo treatments.

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Sleep Disturbance and Its Association with Pain Severity and Multisite Pain: A Prospective 10.7-Year Study.

Sleep disturbance is often comorbid with chronic pain disorders, with emerging evidence suggesting a stronger effect of sleep disturbance on pain than vice versa; however, few studies have evaluated the long-term associations between sleep disturbance and pain. This study was to examine the associations of sleep disturbance with knee pain severity, number of painful sites (NPS) and persistent pain in a 10.7-year cohort study.

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Mas-related G protein-coupled receptor D participates in inflammatory pain by promoting NF-κB activation through interaction with TAK1 and IKK complex.

Mas-related G protein-coupled receptor D (MrgprD) is mainly expressed in small-diameter sensory neurons of the dorsal root ganglion (DRG). Results from previous studies suggest that MrgprD participates in mechanical hyperalgesia and nerve injury-induced neuropathic pain. However, it remains elusive whether and how MrgprD is involved in inflammatory pain. Here, we used a mouse model of chronic inflammatory pain established by intraperitoneal administration of lipopolysaccharide (LPS). The LPS injection induced an evident peripheral neuroinflammation and mechanical hyperalgesia in the mice and increased MrgprD expression in the DRG. The LPS administration also augmented the proportion of MrgprD-expressing neurons in the lumbar 4 DRG. Behaviorally, the LPS-induced hypersensitivities to mechanical and cold stimuli, but not to a heat stimulus, were substantially attenuated in Mrgprd-knockout mice compared with wildtype littermates. Mrgprd deletion in DRGs suppressed the LPS-triggered activation of the NF-κB signaling pathway and attenuated LPS-induced up-regulation of pro-inflammatory factors. Moreover, ectopic overexpression of MrgprD in HEK293 cells stably expressing mouse toll-like receptor 4 (TLR4) markedly promoted the LPS-induced NF-κB activation and enhanced NF-κB's DNA-binding activity. Furthermore, MrgprD physically interacted with TGF-β-activated kinase 1 (TAK1) and I-kappa-B-kinase (IKK) complexes, but not with mitogen-activated protein kinases (MAPKs) in mouse DRGs. In macrophage-like RAW 264.7 cells, MrgprD also interacted with TAK1 and IKK complex, and the treatment of MrgprD agonist elicited the activation of NF-κB signaling, but not of mitogen-activated protein kinases (MAPKs) signaling pathway. Our findings indicate that MrgprD facilitates the development of LPS-triggered persistent inflammatory hyperalgesia by promoting canonical NF-κB activation, highlighting the important roles of MrgprD in NF-κB-mediated inflammation and chronic pain.

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Forebrain delta opioid receptors regulate the response of delta agonist in models of migraine and opioid-induced hyperalgesia.

Delta opioid receptor (DOR) agonists have been identified as a promising novel therapy for headache disorders. DORs are broadly expressed in several peripheral and central regions important for pain processing and mood regulation; and it is unclear which receptors regulate headache associated symptoms. In a model of chronic migraine-associated pain using the human migraine trigger, nitroglycerin, we observed increased expression of DOR in cortex, hippocampus, and striatum; suggesting a role for these forebrain regions in the regulation of migraine. To test this hypothesis, we used conditional knockout mice with DORs deleted from forebrain GABAergic neurons (Dlx-DOR), and investigated the outcome of this knockout on the effectiveness of the DOR agonist SNC80 in multiple headache models. In DOR loxP controls SNC80 blocked the development of acute and chronic cephalic allodynia in the chronic nitroglycerin model, an effect that was lost in Dlx-DOR mice. In addition, the anti-allodynic effects of SNC80 were lost in a model of opioid induced hyperalgesia/medication overuse headache in Dlx-DOR conditional knockouts. In a model reflecting negative affect associated with migraine, SNC80 was only effective in loxP controls and not Dlx-DOR mice. Similarly, SNC80 was ineffective in the cortical spreading depression model of migraine aura in conditional knockout mice. Taken together, these data indicate that forebrain DORs are necessary for the action of DOR agonists in relieving headache-related symptoms and suggest that forebrain regions may play an important role in migraine modulation.

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Revisiting the Provision of Pain Neuroscience Education: An Adjunct Intervention for Patients, but a Primary Focus for Clinician Education.

Society is mired in a serious health care crisis regarding the pain and opioid epidemics. Pain neuroscience education (PNE) has gained support in the last 20 years as an intervention to help people manage their chronic pain condition. In this Viewpoint, we argue exercise and movement must be the primary intervention for chronic pain conditions, and PNE or other adjunctive therapies should only be used if they can foster increased exercise and movement participation by the patient. The only time pain education should be the primary focus of a chronic pain management strategy is with students and clinicians to help advance knowledge and skills regarding pain to ultimately enhance care and outcomes for patients. .

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Vulvodynia.

Vulvodynia is a heterogenous, chronic pain condition of unknown etiology that affects 7% to 15% of women. It affects sexual function and quality of life. Vulvodynia can be primary or secondary, localized or generalized, and spontaneous or provoked. Contributing factors for provoked vulvodynia might include vulvovaginal infections, low estrogen states, and underlying anxiety disorder. Generalized vulvodynia likely arises from underlying connective tissue or neurological dysfunction. Vulvodynia treatment must be individualized on the basis of the patient's presentation and physical examination findings. Surgical excision of the vulvar vestibule has high success rates but other modalities showing success include pelvic floor physical therapy and cognitive-behavioral therapy.

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Investigating Pain-Related Avoidance Behavior using a Robotic Arm-Reaching Paradigm.

Avoidance behavior is a key contributor to the transition from acute pain to chronic pain disability. Yet, there has been a lack of ecologically valid paradigms to experimentally investigate pain-related avoidance. To fill this gap, we developed a paradigm (the robotic arm-reaching paradigm) to investigate the mechanisms underlying the development of pain-related avoidance behavior. Existing avoidance paradigms (mostly in the context of anxiety research) have often operationalized avoidance as an experimenter-instructed, low-cost response, superimposed on stimuli associated with threat during a Pavlovian fear conditioning procedure. In contrast, the current method offers increased ecological validity in terms of instrumental learning (acquisition) of avoidance, and by adding a cost to the avoidance response. In the paradigm, participants perform arm-reaching movements from a starting point to a target using a robotic arm, and freely choose between three different movement trajectories to do so. The movement trajectories differ in probability of being paired with a painful electrocutaneous stimulus, and in required effort in terms of deviation and resistance. Specifically, the painful stimulus can be (partly) avoided at the cost of performing movements requiring increased effort. Avoidance behavior is operationalized as the maximal deviation from the shortest trajectory on each trial. In addition to explaining how the new paradigm can help understand the acquisition of avoidance, we describe adaptations of the robotic arm-reaching paradigm for (1) examining the spread of avoidance to other stimuli (generalization), (2) modeling clinical treatment in the lab (extinction of avoidance using response prevention), as well as (3) modeling relapse, and return of avoidance following extinction (spontaneous recovery). Given the increased ecological validity, and numerous possibilities for extensions and/or adaptations, the robotic arm-reaching paradigm offers a promising tool to facilitate the investigation of avoidance behavior and to further our understanding of its underlying processes.

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Oxytocin Elicits Itch Scratching Behavior via Spinal GRP/GRPR System.

Oxytocin (OT), a neuropeptide involved in the regulation of complex social and sexual behavior in mammals, has been proposed as a treatment for a number of psychiatric disorders including pain. It has been well documented that central administration of OT elicits strong scratching and grooming behaviors in rodents. However, these behaviors were only described as symptoms, few studies have investigated their underlying neural mechanisms. Thus, we readdressed this question and undertook an analysis of spinal circuits underlying OT-induced scratching behavior in the present study. We demonstrated that intrathecal OT induced robust but transient hindpaw scratching behaviors by activating spinal OT receptors (OTRs). Combining the pre-clinical and clinical evidence, we speculated that OT-induced scratching may be an itch symptom. Further RNAscope studies revealed that near 80% spinal GRP neurons expressed OTRs. OT activated the expression of mRNA in spinal GRP neurons. Chemical ablation of GRPR neurons significantly reduced intrathecal OT-induced scratching behaviors. Given GRP/GRPR pathway plays an important role in spinal itch transmission, we proposed that OT binds to the OTRs expressed on the GRP neurons, and activates GRP/GRPR pathway to trigger itch-scratching behaviors in mice. These findings provide novel evidence relevant for advancing understanding of OT-induced behavioral changes, which will be important for the development of OT-based drugs to treat a variety of psychiatric disorders.

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A randomized controlled trial of cognitive behavioral therapy compared with diabetes education for diabetic peripheral neuropathic pain.

A randomized controlled trial compared cognitive behavioral therapy (CBT) and diabetes education (ED) as an adjunctive treatment for diabetic peripheral neuropathic pain (DPNP). We examined change from baseline to 12- and 36-week follow-up in overall pain intensity (NRS), neuropathic pain intensity/quality, pain interference, and mental health functioning, among others. Although CBT participants demonstrated improvement in pain intensity NRS, there were no between-condition differences at either follow-up. CBT reduced neuropathic pain intensity at 12-weeks more than ED. At 36-weeks, CBT was superior to ED for improving pain interference and mental health functioning. Results provide evidence of benefit of CBT for DPNP.: NCT00830011.

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CREB Participates in Paclitaxel-Induced Neuropathic Pain Genesis Through Transcriptional Activation of Dnmt3a in Primary Sensory Neurons.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) often occurs in cancer patients treated with antineoplastic drugs. Therapeutic management of CIPNP is very limited, at least in part due to the largely unknown mechanisms that underlie CIPNP genesis. Here, we showed that systemic administration of the chemotherapeutic drug paclitaxel significantly and time-dependently increased the levels of cyclic AMP response element-binding protein (CREB) in dorsal root ganglion (DRG) neurons. Blocking this increase through DRG microinjection of Creb siRNA attenuated paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities. Mimicking this increase through DRG microinjection of the adeno-associated virus 5 expressing full-length Creb mRNA led to enhanced responses to basal mechanical, heat, and cold stimuli in mice in absence of paclitaxel treatment. Mechanically, paclitaxel-induced increase of DRG CREB protein augmented Dnmt3a promoter activity and participated in the paclitaxel-induced upregulation of DNMT3a protein in the DRG. CREB overexpression also elevated the expression of DNMT3a in in vivo and in vitro DRG neurons of naïve mice. Given that DNMT3a is an endogenous instigator of CIPNP and that CREB co-expresses with DNMT3a in DRG neurons, CREB may be a key player in CIPNP through transcriptional activation of the Dnmt3a gene in primary sensory neurons. CREB is thus a likely potential target for the therapeutic management of this disorder.

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Immediate inhibition of spinal secretory phospholipase A2 prevents the pain and elevated spinal neuronal hyperexcitability and neuroimmune regulatory genes that develop with nerve root compression.

Cervical nerve root injury induces a host of inflammatory mediators in the spinal cord that initiate and maintain neuronal hyperexcitability and pain. Secretory phospholipase A2 (sPLA2) is an enzyme that has been implicated as a mediator of pain onset and maintenance in inflammation and neural injury. Although sPLA2 modulates nociception and excitatory neuronal signaling in vitro, its effects on neuronal activity and central sensitization early after painful nerve root injury are unknown. This study investigated whether inhibiting spinal sPLA2 at the time of nerve root compression (NRC) modulates the pain, dorsal horn hyperexcitability, and spinal genes involved in glutamate signaling, nociception, and inflammation that are seen early after injury. Rats underwent a painful C7 NRC injury with immediate intrathecal administration of the sPLA2 inhibitor thioetheramide-phosphorlycholine. Additional groups underwent either injury alone or sham surgery. One day after injury, behavioral sensitivity, spinal neuronal excitability, and spinal cord gene expression for glutamate receptors (mGluR5 and NR1) and transporters (GLT1 and EAAC1), the neuropeptide substance P, and pro-inflammatory cytokines (TNFα, IL1α, and IL1β) were assessed. Treatment with the sPLA2 inhibitor prevented mechanical allodynia, attenuated neuronal hyperexcitability in the spinal dorsal horn, restored the proportion of spinal neurons classified as wide dynamic range, and reduced genes for mGluR5, substance P, IL1α, and IL1β to sham levels. These findings indicate spinal regulation of central sensitization after painful neuropathy and suggest that spinal sPLA2 is implicated in those early spinal mechanisms of neuronal excitability, perhaps via glutamate signaling, neurotransmitters, or inflammatory cascades.

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Reliability and validity of the 6-item Headache Impact Test in chronic migraine from the PROMISE-2 study.

We examined the reliability and validity of the 6-item Headache Impact Test (HIT-6) specifically on patients with chronic migraine (CM) from the PROMISE-2 clinical trial.

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The short-term effects of head-mounted virtual-reality on neuropathic pain intensity in people with spinal cord injury pain: a randomised cross-over pilot study.

Within-subject, randomised cross-over trial.

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Communicating with Youth about Pain: Developmental Considerations.

Pain experiences can negatively impact children and adolescents, leading to trauma symptoms and nonadherence to important health behaviors. Developmentally-tailored communication strategies may mitigate this risk.

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Gray Matter Structural Alterations in Chronic and Episodic Migraine: A Morphometric Magnetic Resonance Imaging Study.

This study evaluates different parameters describing the gray matter structure to analyze differences between healthy controls, patients with episodic migraine, and patients with chronic migraine.

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Spinal neuron-glia-immune interaction in cross-organ sensitization.

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), historically considered as regional gastrointestinal disorders with heightened colonic sensitivity, are increasingly recognized to have concurrent dysfunction of other visceral and somatic organs, such as urinary bladder hyperactivity, leg pain, and skin hypersensitivity. The inter-organ sensory crosstalk is, at large, termed 'cross-organ sensitization'. These organs, anatomically distant from one another, physiologically interlock through projecting their sensory information into dorsal root ganglia (DRG) and then the spinal cord for integrative processing. The fundamental question of how sensitization of colonic afferent neurons conveys nociceptive information to activate primary afferents that innervate distant organs remains ambiguous. In DRG, primary afferent neurons are surrounded by satellite glial cells (SGCs) and macrophage accumulation in response to signals of injury to form neuron-glia-macrophage triad. Astrocytes and microglia are major resident non-neuronal cells in the spinal cord to interact, physically and chemically, with sensory synapses. Cumulative evidence gathered so far indicate the indispensable roles of paracrine/autocrine interactions among neurons, glial cells, and immune cells in sensory cross-activation. Dichotomizing afferents, sensory convergency in the spinal cord, spinal nerve comingling, and extensive sprouting of central axons of primary afferents each has significant roles in the process of cross-organ sensitization, however, more results are required to explain their functional contributions. DRG that are located outside the blood-brain-barrier and reside upstream in the cascade of sensory flow from one organ to the other in cross-organ sensitization could be safer therapeutic targets to produce less central adverse effects.

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An Evolutionary Medicine Perspective on Treatment of Pediatric Functional Abdominal Pain.

In a recent issue, Kovacic et al. analyze data from a randomized sham-controlled trial and show that pretreatment vagal efficiency, an index related to respiratory sinus arrhythmia, is a predictor of pain improvement in adolescents with functional abdominal pain when treated with auricular percutaneous electrical nerve field stimulation. The underlying premise is the polyvagal hypothesis, an explanatory framework for the evolution of the mammalian autonomic nervous system, which proposes that functional gastrointestinal disorders can result from a chronic maladaptive state of autonomic neural control mechanisms after traumatic stress. This is an opportunity for us to stimulate physicians' interest in evolutionary medicine.

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Long-Term Effects of Self-Administered Transcranial Direct Current Stimulation in Episodic Migraine Prevention: Results of a Randomized Controlled Trial.

Migraine is a multifactorial neurovascular disorder, which affects about 12% of the general population. In episodic migraine, the visual cortex revealed abnormal processing, most likely due to decreased preactivation level. Transcranial direct current stimulation (tDCS) is able to modify cortical excitability and might result in an alleviation of migraine occurrence if used repetitively.

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Secondary Headache: Current Update.

The purpose of this paper is to review some of the causes of secondary headache particularly focusing on the subcategories of secondary headache in the International Classification of Headache Disorders, 3rd edition, the clinical features of these headaches, and their associated features and management.

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Socio-demographic and trauma-related predictors of PTSD within 8 weeks of a motor vehicle collision in the AURORA study.

This is the initial report of results from the AURORA multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. We focus on n = 666 participants presenting to EDs following a motor vehicle collision (MVC) and examine associations of participant socio-demographic and participant-reported MVC characteristics with 8-week posttraumatic stress disorder (PTSD) adjusting for pre-MVC PTSD and mediated by peritraumatic symptoms and 2-week acute stress disorder (ASD). Peritraumatic Symptoms, ASD, and PTSD were assessed with self-report scales. Eight-week PTSD prevalence was relatively high (42.0%) and positively associated with participant sex (female), low socioeconomic status (education and income), and several self-report indicators of MVC severity. Most of these associations were entirely mediated by peritraumatic symptoms and, to a lesser degree, ASD, suggesting that the first 2 weeks after trauma may be a uniquely important time period for intervening to prevent and reduce risk of PTSD. This observation, coupled with substantial variation in the relative strength of mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated with more in-depth analyses of the rich and evolving AURORA data.

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The mouse model of fragile X syndrome exhibits deficits in contagious itch behavior.

Individuals with autism spectrum disorders (ASDs) imitate observed behavior less than age-matched and typically developing peers, resulting in deterred learning ability and social interaction. However, this deficit lacks preclinical assessment tools. A previous study has shown that mice exhibit contagious itch behavior while viewing a scratching demonstrator mouse, as opposed to an ambulating demonstrator mouse, but whether autism mouse models imitate observed scratching behavior remains unknown. Here, we investigated contagious itch behavior in the mouse model of fragile X syndrome (FXS), a common form of inherited intellectual disabilities with a high risk for ASDs. We found that the mouse model of FXS shows deficits in contagious itch behavior. Our findings can be used as a new preclinical assessment tool for measuring imitative deficits in the study of neurodevelopmental disorders including FXS.

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eHealth and mHealth psychosocial interventions for youths with chronic illnesses: A systematic review.

An estimated 12.8% of children and adolescents experience chronic health conditions which lead to poor quality of life, adjustment and coping issues, and concurrent mental health problems. Digital health deployment of psychosocial interventions to support youth with chronic illness has become increasingly popular with the advent of the technological advances in the Digital Age.

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Larger Initial Opioid Prescriptions Following Total Joint Arthroplasty Are Associated with Greater Risk of Prolonged Use.

The ongoing U.S. opioid epidemic threatens quality of life and poses substantial economic and safety burdens to opioid abusers and their communities, physicians, and health-care systems. Public health experts have argued that prescription opioids are implicated in this epidemic; however, opioid dosing following surgical procedures remains controversial. The purpose of this study was to evaluate the relationship between initial opioid prescribing following total hip arthroplasty (THA) and total knee arthroplasty (TKA) and the risk and quantity of long-term opioid use.

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Anti-Opioid Antibodies in Individuals Using Chronic Opioid Therapy for Lower Back Pain.

In addition to the risk of developing opioid use disorder (OUD), known side-effects of long-term opioid use include chronic inflammation and hyperalgesia, which may arise from immune responses induced following chronic opioid use. To investigate this hypothesis, blood samples were obtained from individuals with chronic back pain who were either chronically taking prescription opioids or had minimal recent opioid exposure. Patient samples were analyzed using an enzyme-linked immunosorbent assay (ELISA) against hydrocodone- or oxycodone-hapten conjugates to assess the levels of antibodies present in the samples. While no specific response was seen in opioid-naïve subjects, we observed varying levels of anti-opioid IgM antibodies in the exposed subjects. In these subjects, antibody formation was found to be weakly correlated with current reported daily opioid dose. Other drugs of abuse found to elicit an immune response have been shown to generate advanced glycation end-products (AGEs) through reaction with glucose and subsequent modification of self-proteins. Investigations into this potential mechanism of anti-opioid antibody production identified reduced the formation of reactive intermediate species upon norhydrocodone reaction with glucose in comparison with nornicotine, thus identifying potentially important differences in hapten processing to yield the observed adaptive immune response.

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Abuse Liability, Anti-Nociceptive, and Discriminative Stimulus Properties of IBNtxA.

IBNtxA (3-iodobenzoyl naltrexamine) is a novel μ-opioid receptor (MOR) agonist which is structurally related to the MOR antagonist naltrexone. Recent studies suggest IBNtxA preferentially signals through truncated MOR splice variants, resulting in anti-nociception with reduced side effects, including no conditioned place preference (CPP) when tested at a single dose. IBNtxA represents an intriguing lead compound for preclinical drug development targeting truncated MOR splice variants, but further evaluation of its pharmacological profile is necessary. The purpose of this study was to independently verify the antinociceptive properties of IBNtxA and to examine more completely the rewarding properties and discriminative stimulus effects of IBNtxA, allowing broader assessment of IBNtxA as a candidate for further medications development. A dose of 3 mg/kg IBNtxA was equipotent to 10 mg/kg morphine in a hot-plate analgesia assay. In drug discrimination testing using mice trained to discriminate between 3 mg/kg IBNtxA and vehicle, the κ-agonist U-50488 fully substituted for IBNtxA. MOR agonist morphine, δ-agonist SNC162, NOP agonist SCH 221510, and MOR/NOP partial agonist buprenorphine each partially substituted for IBNtxA. IBNtxA up to 3 mg/kg did not produce a place preference in CPP. Pretreatment with 3 mg/kg IBNtxA but not 1 mg/kg IBNtxA attenuated acquisition of place preference for 10 mg/kg morphine. A dose of 3 mg/kg IBNtxA attenuated morphine-induced hyperlocomotion but did not alter naloxone-precipitated morphine withdrawal. Overall, IBNtxA has a complicated opioid receptor pharmacology . These results indicate that IBNtxA produces potent anti-nociception and has low abuse liability, likely driven by substantial κ agonist signaling effects.

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Mas-related G protein-coupled receptor X2 and its activators in dermatologic allergies.

The Mas-related G protein-coupled receptor X2 (MRGPRX2) is a multiligand receptor responding to various exogenous and endogenous stimuli. Being highly expressed on skin mast cells, MRGPRX2 triggers their degranulation and release of proinflammatory mediators, and it promotes multicellular signaling cascades, such as itch induction and transmission in sensory neurons. The expression of MRGPRX2 by skin mast cells and the levels of the MRGPRX2 agonists (eg, substance P, major basic protein, eosinophil peroxidase) are upregulated in the serum and/or skin of patients with inflammatory and pruritic skin diseases, such as chronic spontaneous urticaria or atopic dermatitis. Therefore, MRGPRX2 and its agonists might be potential biomarkers for the progression of cutaneous inflammatory diseases and the response to treatment. In addition, they may represent promising targets for prevention and treatment of signs and symptoms in patients with skin diseases or drug reactions. To assess this possibility, this review explores the role and relevance of MRGPRX2 and its activators in cutaneous inflammatory disorders and chronic pruritus.

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Between-group difference in mean values or changes in pain intensity? Evaluating the distribution of change from baseline in a neuropathic cancer pain clinical trial.

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Binding Mode Exploration of B1 Receptor Antagonists’ by the Use of Molecular Dynamics and Docking Simulation-How Different Target Engagement Can Determine Different Biological Effects.

The kinin B1 receptor plays a critical role in the chronic phase of pain and inflammation. The development of B1 antagonists peaked in recent years but almost all promising molecules failed in clinical trials. Little is known about these molecules' mechanisms of action and additional information will be necessary to exploit the potential of the B1 receptor. With the aim of contributing to the available knowledge of the pharmacology of B1 receptors, we designed and characterized a novel class of allosteric non-peptidic inhibitors with peculiar binding characteristics. Here, we report the binding mode analysis and pharmacological characterization of a new allosteric B1 antagonist, DFL20656. We analyzed the binding of DFL20656 by single point mutagenesis and radioligand binding assays and we further characterized its pharmacology in terms of IC, B1 receptor internalization and in vivo activity in comparison with different known B1 antagonists. We highlighted how different binding modes of DFL20656 and a Merck compound (compound 14) within the same molecular pocket can affect the biological and pharmacological properties of B1 inhibitors. DFL20656, by its peculiar binding mode, involving tight interactions with N114, efficiently induced B1 receptor internalization and evoked a long-lasting effect in an in vivo model of neuropathic pain. The pharmacological characterization of different B1 antagonists highlighted the effects of their binding modes on activity, receptor occupancy and internalization. Our results suggest that part of the failure of most B1 inhibitors could be ascribed to a lack of knowledge about target function and engagement.

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Pain, Depression, and PTSD Following Major Extremity Trauma Among United States Military Serving in Iraq and Afghanistan: Results from the METALS Study.

Assess the burden and co-occurrence of pain, depression, and posttraumatic stress disorder (PTSD) among service members who sustained a major limb injury, and examine whether these conditions are associated with functional outcomes.

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“Short- and mid-term effects of adding upper cervical manual therapy to a conventional physical therapy program in patients with chronic mechanical neck pain. Randomized controlled clinical trial.”

To evaluate the effect of adding an Upper Cervical Translatoric Mobilization (UCTM) or an Inhibitory Suboccipital Technique (IST) to a physiotherapy treatment in the symptomatology and function of mechanical chronic neck pain patients.

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(E)-3-Furan-2-yl—tolyl-acrylamide and its Derivative DM489 Decrease Neuropathic Pain in Mice Predominantly by α7 Nicotinic Acetylcholine Receptor Potentiation.

The main objective of this study was to determine whether ()-3-furan-2-yl—tolyl-acrylamide (PAM-2) and its structural derivative DM489 produce anti-neuropathic pain activity using the streptozotocin (STZ)- and oxaliplatin-induced neuropathic pain animal models. To assess possible mechanisms of action, the pharmacological activity of these compounds was determined at α7 and α9α10 nicotinic acetylcholine receptors (nAChRs) and Ca2.2 channels expressed alone or coexpressed with G protein-coupled GABA receptors. The animal results indicated that a single dose of 3 mg/kg PAM-2 or DM489 decreases STZ-induced neuropathic pain in mice, and chemotherapy-induced neuropathic pain is decreased by PAM-2 (3 mg/kg) and DM489 (10 mg/kg). The observed anti-neuropathic pain activity was inhibited by the α7-selective antagonist methyllycaconitine. The coadministration of oxaliplatin with an inactive dose (1 mg/kg) of PAM-2 decreased the development of neuropathic pain after 14, but not 7, days of cotreatment. The electrophysiological results indicated that PAM-2 potentiates human (h) and rat (r) α7 nAChRs with 2-7 times higher potency than that for hCa2.2 channel inhibition and an even greater difference compared to that for rα9α10 nAChR inhibition. These results support the notion that α7 nAChR potentiation is likely the predominant molecular mechanism underlying the observed anti-nociceptive pain activity of these compounds.

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Musculoskeletal findings on MRI among postpartum women with persistent pelvic pain.

Persistent postpartum pelvic pain affects one in six women, and its source is often unexplained in the absence of obvious clinical findings. Musculoskeletal injuries during childbirth are common and can be detected using MRI or US; however, pelvic imaging is not standard of care in evaluating women with persistent pain. We hypothesize that clinical symptoms in women with unexplained persistent postpartum pelvic pain will correlate with musculoskeletal abnormalities identified on MRI in > 50% of cases.

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A protocol for chronic pain outcome measurement enhancement by linking PROMIS-29 scale to legacy measures and improving chronic pain stratification.

Substantial investment has gone into research on the efficacy and effectiveness of pharmaceutical and nonpharmacologic interventions for chronic pain. However, synthesizing this extensive literature is challenging because of differences in the outcome measures used in studies of similar or competing interventions. The absence of a common metric makes it difficult to replicate findings, pool data from multiple studies, resolve conflicting conclusions, or reach consensus when interpreting findings.

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Pain modulatory properties of Phoneutria nigriventer crude venom and derived peptides: A double-edged sword.

Phoneutria nigriventer venom (PNV) is a complex mixture of toxins exerting multiple pharmacological effects that ultimately result in severe local pain at the site of the bite. It has been proposed that the PNV-induced pain is mediated by both peripheral and central mechanisms. The nociception triggered by PNV is peripherally mediated by the activation of B, 5-HT, NMDA, AMPA, NK, and NK receptors, as well as TTXS-Na, ASIC, and TRPV1 channels. The activation of tachykinin, glutamate and CGRP receptors along with the production of inflammatory mediators are, at least partially, responsible for the central component of pain. Despite its well established pro-nociceptive properties, PNV contains some toxins with antinociceptive activity, which have been studied in the last few years. The toxins ω-CNTX-Pn4a, ω-CNTX-Pn2a, ω-CNTX-Pn3a, κ-CNTX-Pn1a, U-CNTX-Pn1a, δ-CNTX-Pn1a, and Γ-CNTX-Pn1a from PNV, as well as the semi-synthetic peptide PnPP-19 have been tested in different experimental models of pain showing consistent antinociceptive properties. This review aims to discuss the pro- and antinociceptive actions of PNV and its toxins, highlighting possible mechanisms involved in these apparently dualistic properties.

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Why do some people with severe chronic pain adhere to walking prescriptions whilst others won’t? A cross-sectional study exploring clinical and psychosocial predictors in women with fibromyalgia.

Fibromyalgia (FM) is a highly disabling condition characterized by widespread chronic pain. Physical exercise, such as walking, has been recommended as the treatment of choice for FM. However, adherence to physical exercise tends to be poor. Pain is one of the main inhibitors to adhere to walking in FM patients. The main objective of this study has been to determine whether there is a clinical and psychosocial profile to help predict individual differences in adherence to walking in a sample of patients with FM with severe pain levels. In this cross-sectional study, the sample was composed of 172 women with FM and severe pain levels (> 7 in an 11-point numerical scale). Women were classified into two groups: (1) those who walked regularly and (2) patients who rarely or never walked. Group differences regarding clinical outcomes (e.g., FM impact, anxiety, depression, cognitive fusion, catastrophizing, affect, and personality), sociodemographic variables, and medical history were analyzed. Patients who walked despite pain significantly reported less impact of FM, anxiety, depression, catastrophizing, cognitive fusion, negative affect, openness to experience, agreeableness, and conscientiousness. The unique predictors of group membership (walking versus no walking) in a binary regression were FM impact and negative affect. The results show that adherence to exercise might be influenced and predicted by the clinical profile of the patient, which suggests that personalized motivational interventions should be addressed to this at-risk subgroup.

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