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Papers: 29 Aug 2020 - 4 Sep 2020

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Transcriptional Reprogramming of Distinct Peripheral Sensory Neuron Subtypes after Axonal Injury.

Primary somatosensory neurons are specialized to transmit specific types of sensory information through differences in cell size, myelination, and the expression of distinct receptors and ion channels, which together define their transcriptional and functional identity. By profiling sensory ganglia at single-cell resolution, we find that all somatosensory neuronal subtypes undergo a similar transcriptional response to peripheral nerve injury that both promotes axonal regeneration and suppresses cell identity. This transcriptional reprogramming, which is not observed in non-neuronal cells, resolves over a similar time course as target reinnervation and is associated with the restoration of original cell identity. Injury-induced transcriptional reprogramming requires ATF3, a transcription factor that is induced rapidly after injury and necessary for axonal regeneration and functional recovery. Our findings suggest that transcription factors induced early after peripheral nerve injury confer the cellular plasticity required for sensory neurons to transform into a regenerative state.

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Predicting functional effects of missense variants in voltage-gated sodium and calcium channels.

Malfunctions of voltage-gated sodium and calcium channels (encoded by and family genes, respectively) have been associated with severe neurologic, psychiatric, cardiac, and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) that often corresponds not only to clinical disease manifestations but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. On the basis of known gene-disease mechanisms of 19 different diseases, we inferred LOF ( = 518) and GOF ( = 309) likely pathogenic variants from the disease phenotypes of variant carriers. By training a machine learning model on sequence- and structure-based features, we predicted LOF or GOF effects [area under the receiver operating characteristics curve (ROC) = 0.85] of likely pathogenic missense variants. Our LOF versus GOF prediction corresponded to molecular LOF versus GOF effects for 87 functionally tested variants in and (ROC = 0.73) and was validated in exome-wide data from 21,703 cases and 128,957 controls. We showed respective regional clustering of inferred LOF and GOF nucleotide variants across the alignment of the entire gene family, suggesting shared pathomechanisms in the family genes.

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Brain gray matter abnormalities in osteoarthritis pain: a cross-sectional evaluation.

The interaction between osteoarthritis (OA) pain and brain properties remains minimally understood, although anatomical and functional neuroimaging studies suggest that OA, similar to other chronic pain conditions, may impact as well as partly be determined by brain properties. Here, we studied brain gray matter (GM) properties in OA patients scheduled to undergo total joint replacement surgery. We tested the hypothesis that brain regional GM volume is distinct between hip OA (HOA) and knee OA (KOA) patients, relative to healthy controls and moreover, that these properties are related to OA pain. Voxel-based morphometry group contrasts showed lower anterior cingulate GM volume only in HOA. When we reoriented the brains (flipped) to examine the hemisphere contralateral to OA pain, precentral GM volume was lower in KOA and HOA, and 5 additional brain regions showed distortions between groups. These GM changes, however, did not reflect clinical parameters. Next, we subdivided the brain into larger regions, approximating Brodmann areas, and performed univariable and machine learning-based multivariable contrasts. The univariable analyses approximated voxel-based morphometry results. Our multivariable model distinguished between KOA and controls, was validated in a KOA hold-out sample, and generalized to HOA. The multivariable model in KOA, but not HOA, was related to neuropathic OA pain. These results were mapped into term space (using Neurosynth), providing a meta-analytic summary of brain anatomical distortions in OA. Our results indicate more subtle cortical anatomical differences in OA than previously reported and also emphasize the interaction between OA pain, namely its neuropathic component, and OA brain anatomy.

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Sex Differences in Interleukin-6 Responses Over Time Following Laboratory Pain Testing Among Patients With Knee Osteoarthritis.

Epidemiological studies suggest that women are not only at a higher risk for developing knee osteoarthritis (KOA), but also report greater symptom severity compared to men. One potential underlying mechanism of these sex differences may be exaggerated inflammatory responses to pain among women compared to men. The present study examined sex differences in interleukin-6 (IL-6) response over time following experimental pain testing. We hypothesized that women, when compared to men, would show greater IL-6 reactivity when exposed to acute pain in a human laboratory setting. Eighty-four participants (36 men and 48 women) with KOA scheduled for total knee arthroplasty underwent a quantitative sensory testing (QST) battery. A total of seven IL-6 measurements were taken, twice at baseline, once immediately after QST, and every 30 minutes up to 2 hours after QST. Consistent with our hypothesis, women, when compared to men, showed accelerated increases in IL-6 levels following laboratory-evoked pain, even after controlling for body mass index, marital status, clinical pain, evoked pain sensitivity, and situational pain catastrophizing. Given that KOA is a chronic condition, and individuals with KOA frequently experience pain, these sex differences in IL-6 reactivity may contribute to the maintenance and/or exacerbation of KOA symptoms. PERSPECTIVES: The present study demonstrates that women, when compared to men, exhibit greater IL-6 reactivity after exposure to laboratory-evoked pain. Such sex differences may explain the mechanisms underlying women's higher chronic pain risk and pain perception, as well as provide further insight in developing personalized pain interventions.

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Cav3.2 T-type calcium channels control acute itch in mice.

Cav3.2 T-type calcium channels are important mediators of nociceptive signaling, but their roles in the transmission of itch remains poorly understood. Here we report a key involvement of these channels as key modulators of itch/pruritus-related behavior. We compared scratching behavior responses between wild type and Cav3.2 null mice in models of histamine- or chloroquine-induced itch. We also evaluated the effect of the T-type calcium channel blocker DX332 in male and female wild-type mice injected with either histamine or chloroquine. Cav3.2 null mice exhibited decreased scratching responses during both histamine- and chloroquine-induced acute itch. DX332 co-injected with the pruritogens inhibited scratching responses of male and female mice treated with either histamine or chloroquine. Altogether, our data provide strong evidence that Cav3.2 T-type channels exert an important role in modulating histamine-dependent and -independent itch transmission in the primary sensory afferent pathway, and highlight these channels as potential pharmacological targets to treat pruritus.

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Pain phenotypes classified by machine learning using electroencephalography features.

Pain is a multidimensional experience mediated by distributed neural networks in the brain. To study this phenomenon, EEGs were collected from 20 subjects with chronic lumbar radiculopathy, 20 age and gender matched healthy subjects, and 17 subjects with chronic lumbar pain scheduled to receive an implanted spinal cord stimulator. Analysis of power spectral density, coherence, and phase-amplitude coupling using conventional statistics showed that there were no significant differences between the radiculopathy and control groups after correcting for multiple comparisons. However, analysis of transient spectral events showed that there were differences between these two groups in terms of the number, power, and frequency-span of events in a low gamma band. Finally, we trained a binary support vector machine to classify radiculopathy versus healthy subjects, as well as a 3-way classifier for subjects in the 3 groups. Both classifiers performed significantly better than chance, indicating that EEG features contain relevant information pertaining to sensory states, and may be used to help distinguish between pain states when other clinical signs are inconclusive.

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No pain, still gain (of function): the relation between sensory profiles and the presence or absence of self-reported pain in a large multicenter cohort of patients with neuropathy.

The pathophysiology of pain in neuropathy is complex and may be linked to sensory phenotypes. Quantitative sensory testing, a standardized method to evaluate sensory profiles in response to defined stimuli, assesses functional integrity of small and large nerve fiber afferents and central somatosensory pathways. It has revealed detailed insights into mechanisms of neuropathy, yet, it remains unclear if pain directly affects sensory profiles. The main objective of this study was to investigate sensory profiles in patients with various neuropathic conditions, including polyneuropathy, mononeuropathy, and lesions to the central nervous system, in relation to self-reported presence or absence of pain and pain sensitivity using the Pain Sensitivity Questionnaire.A total of 443 patients (332 painful and 111 painless) and 112 healthy participants were investigated. Overall, loss of sensation was equally prevalent in patients with and without spontaneous pain. Pain thresholds were equally lowered in both patient groups, demonstrating that hyperalgesia and allodynia is just as present in patients not reporting any pain. Remarkably, this was similar for dynamic mechanical allodynia. Hypoalgesia was more pronounced in painful polyneuropathy whereas hyperalgesia was more frequent in painful mononeuropathy (compared to painless conditions). Self-reported pain sensitivity was significantly higher in painful than in painless neuropathic conditions.Our results reveal the presence of hyperalgesia and allodynia in patients with central and peripheral lesions of the somatosensory system not reporting spontaneous pain. This shows that symptoms and signs of hypersensitivity may not necessarily coincide, and that painful and painless neuropathic conditions may mechanistically blend into one another.

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Virtual reality approaches to pain: toward a state of the science.

This brief review provides a summary of existing research on virtual reality (VR) applications to pain. We distinguish three categories of studies – VR applications to clinical acute pain, chronic pain, and acute experimental pain, which are currently equally represented in the literature. The review highlights specific advancements in VR pain research as well as areas in need of more development in scrutiny. In particular, we note the pressing need for theoretical scaffolding to facilitate replicable, theoretically-driven methodology, communication, and advancements across the field. To that end, we provide a preliminary heuristic model of VR application to pain experience. The model distinguishes three categories of factors inherent in VR application to pain: VR Configuration Factors, User Experiential Factors, and Pain Targets and Outcomes. VR Configuration Factors comprise technical input devices, system processes, and output devices, which present a virtual world to the user and enable User Experiential Factors of presence, interactivity, immersion, and embodiment. These interdependent experiential factors serve as potential mediators and moderators for subsequent changes in cognitive, emotional, social, behavioral, and physiological outcomes that serve as Targets of pain-related therapy. Given that rapid technological progress can both facilitate and frustrate research progress within the field, systematic, theoretically-informed inquiry into factors comprising and driving the effects of VR pain applications, combined with more rigorous theoretically-informed methodology, is a critical challenge.

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HDAC3 in hippocampus contributes to memory impairment following chronic constriction injury of sciatic nerve in mice.

Chronic neuropathic pain is frequently accompanied by memory impairment, yet the underlying mechanisms remain unclear. Here we showed that mice displayed memory impairment starting at 14 days and lasting for at least 21 days after chronic constriction injury (CCI) of unilateral sciatic nerve in mice. Systemic administration of the pan histone deacetylase (HDAC) inhibitor sodium butyrate attenuated this memory impairment. More specifically, we found that hippocampus HDAC3 was involved in this process because the levels of its mRNA and protein increased significantly in the hippocampus at 14 and 21 days after CCI, but not sham surgery. Systemic administration of the selective HDAC3 antagonist RGPF966 attenuated CCI-induced memory impairment, improved hippocampal long-term potentiation impairment and rescued reductions of dendritic spine density and synaptic plasticity-associated protein in the hippocampus. Additionally, HDAC3 overexpression in the hippocampus led to memory impairment without affecting basal nociceptive responses in naive mice. Our findings suggest that HDAC3 contributes to memory impairment after CCI by impairing synaptic plasticity in hippocampus. HDAC3 might serve as a potential molecular target for therapeutic treatment of memory impairment under neuropathic pain conditions.

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The STarT Back stratified care model for non-specific low back pain: a model-based evaluation of long-term cost-effectiveness.

The STarT Back approach comprises subgrouping low back pain (LBP) patients according to risk of persistent LBP-related disability, with appropriate matched treatments. In a twelve-month clinical trial and implementation study, this stratified care approach was clinically and cost-effective compared to usual, non-stratified care. Despite the chronic nature of LBP and associated economic burden, model-based economic evaluations in LBP are rare and have shortcomings. This study therefore produces a de-novo decision model of this stratified care approach for LBP management to estimate the long-term cost-effectiveness and address methodological concerns in LBP modelling.A cost-utility analysis from the NHS perspective compared stratified care with usual care in patients consulting in primary care with non-specific LBP. A Markov state-transition model was constructed where patient prognosis over ten years was dependent upon physical function achieved at twelve months. Data from the clinical trial and implementation study provided short term model parameters, with extrapolation using two cohort studies of usual care in LBP.Base-case results indicate this model of stratified care is cost-effective, delivering 0.14 additional quality-adjusted life years (QALYs) at a cost-saving of £135.19 per patient over a time horizon of ten-years. Sensitivity analyses indicate the approach is likely to be cost-effective in all scenarios, and cost-saving in most.It is likely this stratified care model will help reduce unnecessary healthcare usage whilst improving patient quality of life. Whilst decision analytic modelling is employed in many conditions, its use has been underexplored in LBP and this paper also addresses associated methodological challenges.

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Foxo1 selectively regulates static mechanical pain by interacting with Nav1.7.

Mechanical allodynia is a debilitating condition for millions of patients with chronic pain. Mechanical allodynia can manifest in distinct forms, including brush-evoked dynamic and filament-evoked static allodynia. In the nervous system, the forkhead protein Foxo1 plays a critical role in neuronal structures and functions. However, the role of Foxo1 in the somatosensory signal remains unclear. Here, we found that Foxo1 selectively regulated static mechanical pain. Foxo1 knockdown decreased sensitivity to static mechanical stimuli in normal rats and attenuated static mechanical allodynia in rat models for neuropathic, inflammatory, and chemotherapy pain. Conversely, Foxo1 overexpression selectively enhanced sensitivity to static mechanical stimuli and provoked static mechanical allodynia. Furthermore, Foxo1 interacted with voltage gated sodium Nav1.7 channels and increased the Nav1.7 current density by accelerating activation rather than by changing the expression of Nav1.7 in dorsal root ganglia neurons. In addition, the serum level of Foxo1 was found to be increased in chronic pain patients and to be positively correlated with the severity of chronic pain. Altogether, our findings suggest that serum Foxo1 level could be used as a biological marker for prediction and diagnosis of chronic pain. Moreover, selective blockade of Foxo1/Nav1.7 interaction may offer a new therapeutic approach in patients with mechanical pain.

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Spinal cord injury pain.

Spinal cord injury pain encompasses musculoskeletal and neuropathic pain. Its management is often multidisciplinary and involves specific drugs such as antidepressants and antiepileptics, and nonpharmacological treatment including psychotherapy, physical therapy and neuromodulation techniques. Recent progress in the diagnosis, assessment, and understanding of its mechanisms offers the perspective of a more rational therapeutic management, which should result in better therapeutic outcome.

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Opportunities and limitations of genetically modified nonhuman primate models for neuroscience research.

The recently developed new genome-editing technologies, such as the CRISPR/Cas system, have opened the door for generating genetically modified nonhuman primate (NHP) models for basic neuroscience and brain disorders research. The complex circuit formation and experience-dependent refinement of the human brain are very difficult to model in vitro, and thus require use of in vivo whole-animal models. For many neurodevelopmental and psychiatric disorders, abnormal circuit formation and refinement might be at the center of their pathophysiology. Importantly, many of the critical circuits and regional cell populations implicated in higher human cognitive function and in many psychiatric disorders are not present in lower mammalian brains, while these analogous areas are replicated in NHP brains. Indeed, neuropsychiatric disorders represent a tremendous health and economic burden globally. The emerging field of genetically modified NHP models has the potential to transform our study of higher brain function and dramatically facilitate the development of effective treatment for human brain disorders. In this paper, we discuss the importance of developing such models, the infrastructure and training needed to maximize the impact of such models, and ethical standards required for using these models.

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Distinct age dependent C fibre driven oscillatory activity in the rat somatosensory cortex.

When skin afferents are activated, the sensory signals are transmitted to the spinal cord and eventually reach the primary somatosensory cortex (SI), initiating the encoding of the sensory percept in the brain. While subsets of primary afferents mediate specific somatosensory information from an early age, the subcortical pathways that transmit this information undergo striking changes over the first weeks of life, reflected in the gradual emergence of specific sensory behaviours. We therefore hypothesised that this period is associated with differential changes in the encoding of incoming afferent volleys in SI. To test this, we compared SI responses to A fibre skin afferent stimulation and A+C skin afferent fibre stimulation in lightly anaesthetised male rats at postnatal day (P) 7, 14, 21 and 30. Differences in SI activity following A and A+C fibre stimulation changed dramatically over this period. At P30, A+C fibre stimulation evoked significantly larger gamma, beta and alpha energy increases compared to A fibre stimulation alone. At younger ages, the changes in S1 oscillatory activity evoked by the two afferent volleys were not significantly different. Silencing TRPV1+ C fibres with QX-314 significantly reduced the gamma and beta SI oscillatory energy increases evoked by A+C fibres, at P30 and P21, but not at younger ages. Thus, C fibres differentially modulate SI oscillatory activity only from the third postnatal week, well after the functional maturation of the somatosensory cortex. This age-related change in afferent evoked S1 oscillatory activity may underpin the maturation of sensory discrimination in the developing brain. Behavioural responses to sensory stimulation of the skin undergo major developmental changes over the first postnatal weeks. Here we show that this is accompanied by a shift in the differential frequency encoding of sensory A fibre and C fibre afferent inputs into the developing rat somatosensory cortex. The results demonstrate major postnatal changes in the ability of the cortex to differentiate between afferent sensory inputs arriving in the mammalian brain.

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Critical NIH Resources to Advance Therapies for Pain: Preclinical Screening Program and Phase II Human Clinical Trial Network.

Opioid-related death and overdose have now reached epidemic proportions. In response to this public health crisis, the National Institutes of Health (NIH) launched the Helping to End Addiction Long-term Initiative, or NIH HEAL Initiative, an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. Herein, we describe two NIH HEAL Initiative programs to accelerate development of non-opioid, non-addictive pain treatments: The Preclinical Screening Platform for Pain (PSPP) and Early Phase Pain Investigation Clinical Network (EPPIC-Net). These resources are provided at no cost to investigators, whether in academia or industry and whether within the USA or internationally. Both programs consider small molecules, biologics, devices, and natural products for acute and chronic pain, including repurposed and combination drugs. Importantly, confidentiality and intellectual property are protected. The PSPP provides a rigorous platform to identify and profile non-opioid, non-addictive therapeutics for pain. Accepted assets are evaluated in in vitro functional assays to rule out opioid receptor activity and to assess abuse liability. In vivo pharmacokinetic studies measure plasma and brain exposure to guide the dose range and pretreatment times for the side effect profile, efficacy, and abuse liability. Studies are conducted in accordance with published rigor criteria. EPPIC-Net provides academic and industry investigators with expert infrastructure for phase II testing of pain therapeutics across populations and the lifespan. For assets accepted after a rigorous, objective scientific review process, EPPIC-Net provides clinical trial design, management, implementation, and analysis.

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Erenumab does not alter cerebral hemodynamics and endothelial function in migraine without aura.

To assess whether erenumab influences cerebral vasomotor reactivity and flow-mediated dilation in migraine patients.

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The Atlas of Inflammation Resolution (AIR).

Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi- and interdisciplinary approach necessary. The Atlas of Inflammation Resolution (AIR) is a web-based resource capturing an essential part of the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. By mapping experimental data onto the AIR, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The AIR was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses. The AIR is accessible through https://air.bio.informatik.uni-rostock.de.

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National Patterns in Prescription Opioid Use and Misuse Among Cancer Survivors in the United States.

Prescription opioids are frequently prescribed to treat cancer-related pain. However, limited information exists regarding rates of prescription opioid use and misuse in populations with cancer.

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Ultraflexible organic light-emitting diodes for optogenetic nerve stimulation.

Organic electronic devices implemented on flexible thin films are attracting increased attention for biomedical applications because they possess extraordinary conformity to curved surfaces. A neuronal device equipped with an organic light-emitting diode (OLED), used in combination with animals that are genetically engineered to include a light-gated ion channel, would enable cell type-specific stimulation to neurons as well as conformal contact to brain tissue and peripheral soft tissue. This potential application of the OLEDs requires strong luminescence, well over the neuronal excitation threshold in addition to flexibility. Compatibility with neuroimaging techniques such as MRI provides a method to investigate the evoked activities in the whole brain. Here, we developed an ultrathin, flexible, MRI-compatible OLED device and demonstrated the activation of channelrhodopsin-2-expressing neurons in animals. Optical stimulation from the OLED attached to nerve fibers induced contractions in the innervated muscles. Mechanical damage to the tissues was significantly reduced because of the flexibility. Owing to the MRI compatibility, neuronal activities induced by direct optical stimulation of the brain were visualized using MRI. The OLED provides an optical interface for modulating the activity of soft neuronal tissues.

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Patient education materials for non-specific low back pain and sciatica: a protocol for a systematic review and meta-analysis.

Low back pain accounts for more disability than any other musculoskeletal condition and is associated with severe economic burden. Patients commonly present with negative beliefs about low back pain and this can have detrimental effects on their health outcomes. Providing evidence-based, patient-centred education that meets patient needs could help address these negative beliefs and alleviate the substantial low back pain burden. The primary aim of this review is to investigate the effectiveness of patient education materials on immediate process, clinical and health system outcomes.

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ß2-Arrestin germline knockout does not attenuate opioid respiratory depression.

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Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) with monoclonal antibodies in migraine prevention: a brief review.

Interest is growing in the role of pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific PAC1 receptor in migraine and in their antagonism as a strategy for migraine prevention.

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Soluble Epoxide Hydrolase Regulation of Lipid Mediators Limits Pain.

The role of lipids in pain signaling is well established and built on decades of knowledge about the pain and inflammation produced by prostaglandin and leukotriene metabolites of cyclooxygenase and lipoxygenase metabolism, respectively. The analgesic properties of other lipid metabolites are more recently coming to light. Lipid metabolites have been observed to act directly at ion channels and G protein-coupled receptors on nociceptive neurons as well as act indirectly at cellular membranes. Cytochrome P450 metabolism of specifically long-chain fatty acids forms epoxide metabolites, the epoxy-fatty acids (EpFA). The biological role of these metabolites has been found to mediate analgesia in several types of pain pathology. EpFA act through a variety of direct and indirect mechanisms to limit pain and inflammation including nuclear receptor agonism, limiting endoplasmic reticulum stress and blocking mitochondrial dysfunction. Small molecule inhibitors of the soluble epoxide hydrolase can stabilize the EpFA in vivo, and this approach has demonstrated relief in preclinical modeled pain pathology. Moreover, the ability to block neuroinflammation extends the potential benefit of targeting soluble epoxide hydrolase to maintain EpFA for neuroprotection in neurodegenerative disease.

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Clinical characterization of delayed alcohol-induced headache: A study of 1,108 participants.

To evaluate the International Classification of Headache Disorders (ICHD) criteria and characterize the clinical phenotype of delayed alcohol-induced headache (DAIH).

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What Is the Effectiveness of Different Duration Interdisciplinary Treatment Programs in Patients with Chronic Pain? A Large-Scale Longitudinal Register Study.

Chronic pain is a leading cause of disability globally. Interdisciplinary multimodal pain rehabilitation (IMPR) targets pain with a bio-psycho-social approach, often delivered as composite programs. However, evidence of optimal program duration for the rehabilitation to succeed remains scarce. This study evaluated the effectiveness of different duration IMPR-programs-using within- and between-effects analyses in a pragmatic multicenter register-based controlled design. Using the Swedish Quality Registry for Pain Rehabilitation, data from fifteen clinics specialized in chronic pain rehabilitation across Sweden were retrieved. Participants were patients with chronic musculoskeletal pain who had taken part in short (4-9 weeks; = 924), moderate (10 weeks; = 1379), or long (11-18 weeks; = 395) IMPR programs. Longitudinal patient-reported outcome data were assessed at baseline, post-intervention, and at a 12-month follow-up. Primary outcomes were health-related quality of life, presented as perceived physical and mental health (SF-36). Secondary outcomes included the Hospital Anxiety and Depression Scale (HADS), pain intensity (NRS 0-10), the Multidimensional Pain Inventory (MPI), and perceived health (EQ-5D). Overall, all groups showed improvements. No clinically important effect emerged for different duration IMPR. In conclusion, while our results showed that patients following IMPR report improvement across a bio-psycho-social specter, a longer program duration was no more effective than a shorter one.

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Assessing Digital Health Implementation for a Pediatric Chronic Pain Intervention: Comparing the RE-AIM and BIT Frameworks Against Real-World Trial Data and Recommendations for Future Studies.

Digital health interventions have demonstrated efficacy for several conditions including for pediatric chronic pain. However, the process of making interventions available to end users in an efficient and sustained way is challenging and remains a new area of research. To advance this field, comprehensive frameworks have been created.

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Understanding parents’ experiences of disease course and influencing factors: a 3-year follow-up qualitative study among parents of children with functional abdominal pain.

Functional abdominal pain is a common symptom in children and adolescents. Three years ago, we investigated the experiences among parents whose children had chronic abdominal pain but no somatic diagnosis. The aim of the present follow-up study was to explore those families' current situations.

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Altered pain processing in patients with type 1 and 2 diabetes: systematic review and meta-analysis of pain detection thresholds and pain modulation mechanisms.

The first signs of diabetic neuropathy typically result from small-diameter nerve fiber dysfunction. This review synthesized the evidence for small-diameter nerve fiber neuropathy measured via quantitative sensory testing (QST) in patients with diabetes with and without painful and non-painful neuropathies. Electronic databases were searched to identify studies in patients with diabetes with at least one QST measure reflecting small-diameter nerve fiber function (thermal or electrical pain detection threshold, contact heat-evoked potentials, temporal summation or conditioned pain modulation). Four groups were compared: patients with diabetes (1) without neuropathy, (2) with non-painful diabetic neuropathy, (3) with painful diabetic neuropathy and (4) healthy individuals. Recommended methods were used for article identification, selection, risk of bias assessment, data extraction and analysis. For the meta-analyses, data were pooled using random-effect models. Twenty-seven studies with 2422 participants met selection criteria; 18 studies were included in the meta-analysis. Patients with diabetes without symptoms of neuropathy already showed loss of nerve function for heat (standardized mean difference (SMD): 0.52, p<0.001), cold (SMD: -0.71, p=0.01) and electrical pain thresholds (SMD: 1.26, p=0.01). Patients with non-painful neuropathy had greater loss of function in heat pain threshold (SMD: 0.75, p=0.01) and electrical stimuli (SMD: 0.55, p=0.03) compared with patients with diabetes without neuropathy. Patients with painful diabetic neuropathy exhibited a greater loss of function in heat pain threshold (SMD: 0.55, p=0.005) compared with patients with non-painful diabetic neuropathy. Small-diameter nerve fiber function deteriorates progressively in patients with diabetes. Because the dysfunction is already present before symptoms occur, early detection is possible, which may assist in prevention and effective management of diabetic neuropathy.

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Assessing the role of glycosphingolipids in the phenotype severity of Fabry disease mouse model.

Fabry disease is caused by deficient activity of α-galactosidase A-an enzyme that hydrolyses the terminal α-galactosyl moieties from glycolipids and glycoproteins–and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3) and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb3 isoforms (various fatty acids) and lyso-Gb3 analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb3 and lyso-Gb3 levels in the heart, kidney and dorsal root ganglion (DRG) were similar in two strains. However, levels of the C20-fatty acid isoform of Gb3 and particular lyso-Gb3 analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared to Fabry-B6. By contrast, there was no difference in Gb3 and lyso-Gb3 isoforms/analogs in the kidneys and DRG between two strains. Furthermore, using immunohistochemistry, we found that Gb3 massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb3 accumulation was not observed in non-peptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of non-peptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb3 or lyso-Gb3 may play major roles in the pathogenesis of Fabry disease, and that Gb3 and lyso-Gb3 are not responsible for the pathology in all tissues or cell types.

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Reason to doubt the ICHD-3 7-day inclusion criterion for mild TBI-related posttraumatic headache: A nested cohort study.

Posttraumatic headache is difficult to define and there is debate about the specificity of the 7-day headache onset criterion in the current definition. There is limited evidence available to guide decision making about this criterion.

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Predicting the outcome of the greater occipital nerve block – an observational study on migraine patients with and without musculoskeletal cervical impairment.

The importance of neck pain and the trigeminocervical complex in migraine is of high pathophysiological interest since a block to the greater occipital nerve is more effective for some primary headaches than others. This observational study hypothesised that the response to manual palpation of the upper cervical spine predicts the efficacy of the greater occipital nerve-block.

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Gabapentin in pregnancy and the risk of adverse neonatal and maternal outcomes: A population-based cohort study nested in the US Medicaid Analytic eXtract dataset.

Despite the widespread use, only sparse information is available on the safety of gabapentin during pregnancy. We sought to evaluate the association between gabapentin exposure during pregnancy and risk of adverse neonatal and maternal outcomes.

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MRGPRX2 signals its importance in cutaneous mast cell biology: Does MRGPRX2 connect mast cells and atopic dermatitis?

The discovery of MRGPRX2 marks an important change in MC biology, explaining non-IgE-mediated clinical phenomena relying on MCs. As receptor for multiple drugs, MRGPRX2 is crucial to drug-induced hypersensitivity. However, not only drugs, but also endogenous mediators like neuropeptides and host defense peptides activate MRGPRX2, suggesting its broad impact in cutaneous pathophysiology. Here, we give a brief overview of MRGPRX2 and its regulation by microenvironmental stimuli, which support MCs and can be altered in skin disorders, and briefly touch on the functional programs elicited by MRGPRX2 ligation. Studies in Mrgprb2-deficient mice (the murine ortholog) help illuminate MRGPRX2's function in health and disease. Recent advances in this model support the long-suspected operational unit between MCs and nerves, with MRGPRX2 being a vital component. Based on the limited evidence for a major contribution of FcεRI/IgE-activated MCs to atopic dermatitis (AD), we develop the hypothesis that MRGPRX2 constitutes the missing link connecting MCs and AD, at least in selected endotypes. Support comes from the multifold changes in the MC-neuronal system of AD skin (e.g. greater density of MCs and closer connections between MCs and nerves, increased PAR-2/Substance P). We theorize that these deregulations suffice to initiate AD, but external triggers, many of which activating MRGPRX2 themselves (e.g. Staphylococcus aureus) further feed into the loop. Itch, the most burdensome hallmark of AD, is mostly non-histaminergic but tryptase-dependent, and tryptase is preferentially released upon MRGPRX2 activation. Because MRGPRX2 is a very active research field, some of the existing gaps are likely to be closed soon.

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Perceived validation and criticism in pain: development of a new measure in chronic pain.

Research suggests that the way others react to a pain flare-up impacts on psychological and pain-related symptoms in chronic pain (CP). Experiencing validation from others is associated with less negative emotions and better functioning. Contrarily, experiencing criticism is linked to greater pain intensity and worse functioning. Nonetheless, studies are limited by an exclusive focus on spouses rather than significant other relationships, the use of proxy constructs (e.g., social support, responsiveness, solicitousness) rather than specific measures of validation and criticism, and a focus on significant others' behavior rather than patients' subjective experience. This study examines the psychometric properties of a new measure – Perceived Validation and Criticism in Pain Questionnaire (PVCPQ), and tests its contribution to functional impairment beyond pain intensity, sociodemographic and medical-related variables, positive and negative affect, safeness, and compassion from others.

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Topical application of loperamide/oxymorphindole, mu and delta opioid receptor agonists, reduces sensitization of C-fiber nociceptors that possess Na1.8.

It was recently shown that local injection, systemic administration or topical application of the peripherally-restricted mu-opioid receptor (MOR) agonist loperamide (Lo) and the delta-opioid receptor (DOR) agonist oxymorphindole (OMI) synergized to produce highly potent anti-hyperalgesia that was dependent on both MOR and DOR located in the periphery. We assessed peripheral mechanisms by which this Lo/OMI combination produces analgesia in mice expressing the light-sensitive protein channelrhodopsin2 (ChR2) in neurons that express Na1.8 voltage-gated sodium channels. These mice (Na1.8-ChR2) enabled us to selectively target and record electrophysiological activity from these neurons (the majority of which are nociceptive) using blue light stimulation of the hind paw. We assessed the effect of Lo/OMI on nociceptor activity in both naïve mice and mice treated with complete Freund's adjuvant (CFA) to induce chronic inflammation of the hind paw. Teased fiber recording of tibial nerve fibers innervating the plantar hind paw revealed that the Lo/OMI combination reduced responses to light stimulation in naïve mice and attenuated spontaneous activity as well as responses to light and mechanical stimuli in CFA-treated mice. These results show that Lo/OMI reduces activity of C-fiber nociceptors that express Na1.8 and corroborate recent behavioral studies demonstrating the potent analgesic effects of this drug combination. Because of its peripheral site of action, Lo/OMI might produce effective analgesia without the side effects associated with activation of opioid receptors in the central nervous system.

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Regulators of G protein signalling as pharmacological targets for the treatment of neuropathic pain.

Neuropathic pain, a specific type of chronic pain resulting from persistent nervous tissue lesions, is a debilitating condition that affects about 7% of the population. This condition remains particularly difficult to treat because of the poor understanding of its underlying mechanisms. Drugs currently used to alleviate this chronic pain syndrome are of limited benefit due to their lack of efficacy and the elevated risk of side effects, especially after a prolonged period of treatment. Although drugs targeting G protein-coupled receptors (GPCR) also have several limitations, such as progressive loss of efficacy due to receptor desensitization or unavoidable side effects due to wide receptor distribution, the identification of several molecular partners that contribute to the fine-tuning of receptor activity has raised new opportunities for the development of alternative therapeutic approaches. Regulators of G protein signalling (RGS) act intracellularly by influencing the coupling process and activity of G proteins, and are amongst the best-characterized physiological modulators of GPCR. Changes in RGS expression have been documented in a range of models of neuropathic pain, or after prolonged treatment with diverse analgesics, and could participate in altered pain processing as well as impaired physiological or pharmacological control of nociceptive signals. The present review summarizes the experimental data that implicates RGS in the development of pain with focus on the pathological mechanisms of neuropathic pain, including the impact of neuropathic lesions on RGS expression and, reciprocally, the influence of modifying RGS on GPCRs involved in the modulation of nociception as well as on the outcome of pain. In this context, we address the question of the relevance of RGS as promising targets in the treatment of neuropathic pain.

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The alarmins S100A8 and S100A9 mediate acute pain in experimental synovitis.

Synovitis-associated pain is mediated by inflammatory factors that may include S100A8/9, which is able to stimulate nociceptive neurons via Toll-like receptor 4. In this study, we investigated the role of S100A9 in pain response during acute synovitis.

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Adult brain activation in response to pain is changed by neonatal painful stimulation according to sex: a manganese-enhanced MRI study.

Although it is known that nociceptive stimulation in the first postnatal week in rats is useful to model preterm pain, resulting in activation of specific brain areas, as assessed in vivo using manganese-enhanced magnetic resonance imaging (MEMRI), little is known about its long-term effects and sex specificity. Here we aimed to investigate whether inflammatory pain induced in male and female adult rats modify the pattern of brain activation between animals subjected or not to neonatal pain. For this, Complete Freund's adjuvant (CFA, was injected into the left hind paw of rat pups on postnatal day 1 (P1) or P8 to induce inflammatory response. During adulthood, CFA-treated and control animals were injected with CFA 1 hour prior MRI. MEMRI has the ability to enhance the contrast of selective brain structures in response to a specific stimulus, as the pain. MEMRI responses were consistent with activation of nociceptive pathways and these responses were reduced in animals treated with CFA on P1, but increased in animals treated on P8, mainly in the female group. In agreement, P8 female group showed exacerbated responses in the thermal nociceptive test. By using MEMRI we conclude that the natural ability of adult rats to recognize and react to pain exposition is modified by neonatal painful exposition, mainly among females.

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Prospective application of implementation science theories and frameworks to inform use of PROMs in routine clinical care within an integrated pain network.

The objective of this study is to present the implementation science approaches that were used before implementing electronic patient-reported outcome measures (ePROMs) across an integrated chronic pain network that includes primary, rehabilitation, and hospital-based care.

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The Association of MRI Findings and Long-Term Disability in Patients With Chronic Low Back Pain.

Longitudinal cohort study with 13-year follow-up.

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The dimensions of “failed back surgery syndrome”: what is behind a label?

The term failed back surgery syndrome (FBSS) has been criticized for being too unspecific and several studies have shown that a variety of conditions may underlie this label. The aims of the present study were to describe the specific symptoms and to investigate the primary and secondary underlying causes of FBSS in a contemporary series of patients who had lumbar spinal surgery before.

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Structural and Functional Brain Abnormalities in Trigeminal Neuralgia: A Systematic Review.

To evaluate the available literature on structural and functional brain abnormalities in trigeminal neuralgia (TN) using several brain magnetic resonance imaging (MRI) techniques to further understand the central mechanisms of TN.

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Impact of Spinal Cord Stimulation on Opioid Dose Reduction: A Nationwide Analysis.

Opioid misuse in the USA is an epidemic. Utilization of neuromodulation for refractory chronic pain may reduce opioid-related morbidity and mortality, and associated economic costs.

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Digital health for patients with chronic pain during the COVID-19 pandemic.

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Risk of persistent opioid use following major surgery in matched samples of patients with and without cancer.

The opioid crisis has reached epidemic proportions, yet risk of persistent opioid use following curative intent surgery for cancer and factors influencing this risk are not well understood.

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Complementary and alternative therapies for post-caesarean pain.

Pain after caesarean sections (CS) can affect the well-being of the mother and her ability with her newborn. Conventional pain-relieving strategies are often underused because of concerns about the adverse maternal and neonatal effects. Complementary alternative therapies (CAM) may offer an alternative for post-CS pain.

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Cognitive Impairment in a Classical Rat Model of Chronic Migraine may be due to Alterations in Hippocampal Synaptic Plasticity and NMDA Receptor Subunits.

Although migraine is a major global public health problem, its impact on cognitive abilities remains controversial. Thus, the present study investigated the effects of repeated administration of inflammatory soup (IS) to the dura of rats, over 3 weeks, on spatial cognition, hippocampal synaptic plasticity, and the expression of N-methyl-D-aspartate receptor (NMDAR) subunits. Additionally, low doses of amitriptyline (AMI; 5 mg/kg) were applied to assess its therapeutic effects. The IS group exhibited significant reductions in the cutaneous stimulation threshold, presence of mild cognitive impairment, and decreased long-term potentiation (LTP) in right hippocampus. However, AMI improved pain behaviors, enhanced cognitive function, and increased synaptic plasticity in the IS rats. On the other hand, the administration of AMI to normal rats negatively influenced synaptic plasticity and reduced the expression of NMDAR subunits. The present results indicate that IS-induced dural nociception led to impairments in spatial cognition that could be attributed to reductions in hippocampal LTP and the decreased expression of NMDAR subunits.

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Identifying Predictors of Recommendations for and Participation in Multimodal Nonpharmacological Treatments for Chronic Pain Using Patient-Reported Outcomes and Electronic Medical Records.

High-quality chronic pain care emphasizes multimodal treatments that include medication and nonpharmacological treatments. But it is not clear which patients will participate in nonpharmacological treatments, such as physical therapy or mental health care, and previous research has shown conflicting evidence.

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TRPV1, TRPA1, and TRPM8 are expressed in axon terminals in the cornea: TRPV1 axons contain CGRP and secretogranin II; TRPA1 axons contain secretogranin 3.

The cornea is highly enriched in sensory neurons expressing the thermal TRP channels TRPV1, TRPA1, and TRPM8, and is an accessible tissue for study and experimental manipulation. The aim of this work was to provide a concise characterization of the expression patterns of various TRP channels and vesicular proteins in the mammalian cornea.

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Determining Thresholds for Meaningful Change for the Headache Impact Test (HIT-6) Total and Item-Specific Scores in Chronic Migraine.

The objective of the analyses described here was to develop thresholds defining clinically meaningful response on the total and item scores of the 6-item short-form Headache Impact Test (HIT-6) in a population of patients with chronic migraine (CM).

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CaMK4-dependent phosphorylation of Akt/mTOR underlies Th17 excessive activation in experimental autoimmune prostatitis.

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is a complicated syndrome characterized by genitourinary pain in the absence of bacterial infection. Th17 cell-driven autoimmunity has been proposed as a cause of CP/CPPS. However, the factors that promote Th17-driven autoimmunity in experimental autoimmune prostatitis (EAP) and the molecular mechanisms are still largely unknown. Here, we showed that Th17 cells were excessively activated, and blockade of IL-17A could effectively ameliorate various symptoms in EAP. Furthermore, we revealed that calcium/calmodulin-dependent kinase Ⅳ (CaMK4), especially Thr p-CaMK4 was increased in the Th17 cells of the EAP group, which were activated by intracellular cytosolic Ca . Pharmacologic and genetic inhibition of CaMK4 decreased the proportion of Th17 cells, and the protein and mRNA level of IL-17A, IL-22, and RORγt. The phosphorylation of CaMK4 was dependent on the increase in intracellular cytosolic Ca concentration in Th17 cells. A mechanistic study demonstrated that inhibition of CaMK4 reduced IL-17A production by decreasing the phosphorylation of Akt-mTOR, which was well accepted to positively regulate Th17 differentiation. Collectively, our results demonstrated that Ca -CaMK4-Akt/mTOR-IL-17A axis inhibition may serve as a promising therapeutic strategy for CP/CPPS.

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How and how fast does pain lead to disability? A multilevel mediation analysis on structural, temporal and biopsychosocial pathways in patients with chronic nonspecific low back pain.

Self-efficacy, fear of movement, and depression may mediate the sequential pathway of how pain leads to disability in nonspecific low back pain. Participants with chronic (>13 weeks) non-specific low back pain were included. They were prospectively monitored for eight consecutive weeks. Each second day, all participants filled in a survey (30 surveys pp). Questionnaires on current back pain intensity (NRS) and disability (PDI) were completed in each survey. One out of three standardized questionnaires on self-efficacy (SES), fear of movement, kinesiophobia (TSK), or depression (PHQ-9) were randomly completed each time. Multilevel mediation analyses on the within-(temporal changes) and between-patients total and indirect (mediated by SES; TSK and PHQ-9) effect of pain on disability were conducted for three temporal associations: No time delay, Simple temporal delay, and Double delay. In total, 280 questionnaires were filled in by 10 participants (m = 4; 34.4 ± 12.2 years). A moderate to strong effect of pain on disability in the no delay-model for the within-patients (0.436), and (all models) in the between-patients (0.595-0.627) models was found. The way how pain affects kinesiophobia was influenced by the time passed. Kinesiophobia itself predicted disability. Further, depression was affected by (within and between) pain intensity (NRS). In the simple delay effects mediation, depression affects disability (within) and is itself affected by the pain (between). No indirect effect of self-efficacy, fear of movement and depression in the pain-disability relationship was found. Understanding underlying mechanisms of how and when pain leads to disability might help to find accurate measures in therapy setting.

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Differential glutamatergic and GABAergic contributions to the tetrad effects of Δ-tetrahydrocannabinol revealed by cell-type-specific reconstitution of the CB1 receptor.

Δ-tetrahydrocannabinol (THC), the major psychoactive ingredient of Cannabis sativa, exerts its actions through the endocannabinoid system by stimulation of the cannabinoid type 1 (CB1) receptor. The widespread distribution of this receptor in different neuronal cell types and the plethora of functions that is modulated by the endocannabinoid system explain the versatility of the effects of THC. However, the cell types involved in the different THC effects are still not fully known. Conditional CB1 receptor knock-out mice were previously used to identify CB1 receptor subpopulations that are "necessary" for the tetrad effects of a high dose of THC: hypothermia, hypolocomotion, catalepsy and analgesia. Here, we used mouse models for conditional CB1 receptor "rescue" in dorsal telencephalic glutamatergic and forebrain GABAergic neurons to determine which CB1 receptor subpopulations are "sufficient" for these tetrad effects. Glutamatergic CB1 receptor was not only necessary but also sufficient for THC-induced hypothermia and hypolocomotion. Analgesic and cataleptic effects of THC are largely independent of glutamatergic and GABAergic CB1 receptors, since no sufficiency was found, in agreement with the previously reported lack of necessity. We also revealed a novel aspect of GABAergic CB1 receptor signaling. In animals with CB1 receptors exclusively in forebrain GABAergic neurons, THC stimulated rather than reduced locomotion. This cell-type selective and hitherto unsuspected hyperlocomotive effect may be occluded in wild-types and conditional knockouts and only be exposed when CB1 signaling is absent in all other cell types, thus underlining the importance of investigating both necessary and sufficient functions to unequivocally unravel cell-type specific actions.

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Lasmiditan for Acute Treatment of Migraine in Adults: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

The US Food and Drug Administration has approved orally administered 100-mg and 200-mg doses of lasmiditan for the acute treatment of migraine, with or without aura. Having a unique mechanism of action, lasmiditan is the first and only Food and Drug Administration-approved serotonin 5-HT receptor agonist.

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Current Strategies for the Management of Painful Diabetic Neuropathy.

The development of painful diabetic neuropathy (PDN) is a common complication of chronic diabetes that can be associated with significant disability and healthcare costs. Prompt symptom identification and aggressive glycemic control is essential in controlling the development of neuropathic complications; however, adequate pain relief remains challenging and there are considerable unmet needs in this patient population. Although guidelines have been established regarding the pharmacological management of PDN, pain control is inadequate or refractory in a high proportion of patients. Pharmacotherapy with anticonvulsants (pregabalin, gabapentin) and antidepressants (duloxetine) are common first-line agents. The use of oral opioids is associated with considerable morbidity and mortality and can also lead to opioid-induced hyperalgesia. Their use is therefore discouraged. There is an emerging role for neuromodulation treatment modalities including intrathecal drug delivery, spinal cord stimulation, and dorsal root ganglion stimulation. Furthermore, consideration of holistic alternative therapies such as yoga and acupuncture may augment a multidisciplinary treatment approach. This aim of this review is to focus on the current management strategies for the treatment of PDN, with a discussion of treatment rationale and practical considerations for their implementation.

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Positive allosteric modulation of the cannabinoid type-1 receptor (CB1R) in periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats.

Opioid drugs are a first-line treatment for severe acute pain and other chronic pain conditions, but long-term opioid drug use produces opioid-induced hyperalgesia (OIH). Co-administration of cannabinoids with opioid receptor agonists produce anti-nociceptive synergy, but cannabinoid receptor agonists may also produce undesirable side effects. Therefore, positive allosteric modulators (PAM) of cannabinoid type-1 receptors (CB1R) may provide an option reducing pain and/or enhancing the anti-hyperalgesic effects of opioids without the side effects, tolerance, and dependence observed with the use of ligands that target the orthosteric binding sites. This study tested GAT211, a PAM of cannabinoid type-1 receptors (CB1R), for its ability to enhance the anti-hyperalgesic effects of the mu-opioid receptor (MOR) agonist DAMGO in rats treated chronically with morphine (or saline) and tested during withdrawal. We tested the effects of intra-periaqueductal gray (PAG) injections of (1) DAMGO, (2) GAT211, or (3) DAMGO + GAT211 on thermal nociception in chronic morphine-treated rats that were hyperalgesic and also in saline-treated control rats. We used slice electrophysiology to test the effects of DAMGO/GAT211 bath application on synaptic transmission in the vlPAG. Intra-PAG DAMGO infusions dose-dependently reversed chronic morphine-induced hyperalgesia, but intra-PAG GAT211 did not alter nociception at the doses we tested. When co-administered into the PAG, GAT211 antagonized the anti-nociceptive effects of DAMGO in morphine-withdrawn rats. DAMGO suppressed synaptic inhibition in the vlPAG of brain slices taken from saline- and morphine-treated rats, and GAT211 attenuated DAMGO-induced suppression of synaptic inhibition in vlPAG neurons via actions at CB1R. These findings show that positive allosteric modulation of CB1R antagonizes the behavioral and cellular effects of a MOR agonist in the PAG of rats.

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The prevalence of suicidal behaviour in fibromyalgia patients.

Fibromyalgia (FM) is a condition associated with chronic pain in muscles and soft tissues. Extant literature has demonstrated an association between FM, mood symptoms and suicidal behaviour. This systematic review aims to synthesize available literature assessing the prevalence of suicidality in FM populations and qualitatively review the included articles.

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Effects of Acute Experimental Stress on Pain Sensitivity and Cortisol Levels in Healthy Participants: A Randomized Crossover Pilot Study.

To investigate pain sensitivity in the masseter muscle and index finger in response to acute psychologic stress in healthy participants.

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Rimegepant (Nurtec ODT) for Acute Treatment of Migraine.

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An Adapted Chronic Constriction Injury of the Sciatic Nerve Produces Sensory, Affective, and Cognitive Impairments: A Peripheral Mononeuropathy Model for the Study of Comorbid Neuropsychiatric Disorders Associated with Neuropathic Pain in Rats.

Chronic constriction injury (CCI) is a model of neuropathic pain induced by four loose ligatures around the sciatic nerve. This work aimed to investigate the sensory, affective, cognitive, and motor changes induced by an adaptation of the CCI model by applying a single ligature around the sciatic nerve.

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Withdrawal-associated injury site pain prevalence and correlates among opioid-using people who inject drugs in Vancouver, Canada.

Pain can return temporarily to old injury sites during opioid withdrawal. The prevalence and impact of opioid withdrawal-associated injury site pain (WISP) in various groups is unknown.

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Yoga compared to non-exercise or physical therapy exercise on pain, disability, and quality of life for patients with chronic low back pain: A systematic review and meta-analysis of randomized controlled trials.

Chronic low back pain (CLBP) is a common and often disabling musculoskeletal condition. Yoga has been proven to be an effective therapy for chronic low back pain. However, there are still controversies about the effects of yoga at different follow-up periods and compared with other physical therapy exercises.

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Prevalence, Characteristics, and Management of Chronic Noncancer Pain Among People Who Use Drugs: A Cross-Sectional Study.

Most studies on chronic noncancer pain (CNCP) in people who use drugs (PWUD) are restricted to people attending substance use disorder treatment programs. This study assessed the prevalence of CNCP in a community-based sample of PWUD, identified factors associated with pain, and documented strategies used for pain relief.

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Resveratrol exerts anti-oxidant and anti-inflammatory actions and prevents oxaliplatin-induced mechanical and thermal allodynia.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a frequent and devastating side effect of cancer therapy. No preventive strategies are currently available. We investigated the use of resveratrol (RESV) in the prevention of CIPNP and evaluated key components of the antioxidant defense system and neuroinflammatory factors as possible mediators contributing to RESV actions. Male rats were injected with oxaliplatin (OXA) and received daily oral RESV. Paw mechanical and thermal allodynia, oxidative stress, antioxidant, pro-inflammatory and neuronal injury/activation markers were evaluated in the sciatic nerve (SN), lumbar dorsal root ganglia (DRG) and spinal cord (SC). OXA-injected animals developed mechanical and thermal allodynia, while those receiving OXA+RESV showed patterns of response similar to control animals. Higher TBARS levels and lower GSH/GSSG ratios were observed in the SN of animals receiving OXA. The mRNA levels of the transcription factor NFκB and the pro-inflammatory cytokine TNFα were found to be upregulated both in lumbar DRG and SC. In addition, the antioxidant enzymes NQO-1 and HO-1 and the neuronal injury marker ATF3 showed increased levels of expression in lumbar DRG. In the dorsal SC the neuronal activation marker c-fos and the transcription factor Nrf2, main regulator of antioxidant defenses, were found to be upregulated. RESV early and sustained administration prevented NFκB, TNFα, ATF3 and c-fos upregulation, while increasing the expression of Nrf2, NQO-1, HO-1 and the redox-sensitive deacetylase SIRT1. RESV treatment was also able to restore TBARS levels and GSH/GSSG ratio. Thus, RESV administration resulted in the upregulation of antioxidant mediators, suppression of pro-inflammatory parameters and prevention of OXA-induced mechanical and thermal allodynia.

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Changes in Interventional Pain Physician Decision-Making, Practice Patterns, and Mental Health During the Early Phase of the SARS-CoV-2 Global Pandemic.

The novel coronavirus outbreak (SARS-CoV-2) began in late 2019 and dramatically impacted health care systems. This study aimed to describe the impact of the early phase of the pandemic on physician decision-making, practice patterns, and mental health.

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Autonomy and competence satisfaction as resources for facing chronic pain disability in adolescence: a self-determination perspective.

This study aimed to test empirically the developmental goal pursuit model of paediatric chronic pain, which draws upon Self-Determination Theory for understanding risks and resources for living with chronic pain. This study examined the relationship between basic psychological need satisfaction (i.e. the satisfaction of the needs for autonomy, relatedness and competence) and the fear-avoidance model of pain in adolescents suffering from chronic pain. Hundred and twenty adolescents (mean age = 14.52, 71.6% female), receiving treatment through paediatric pain centres for chronic pain, were enrolled. Adolescents completed measures of basic psychological need satisfaction, fear and avoidance of pain, and pain-related functional impairment. Path analyses model indicated that higher levels of autonomy and competence satisfaction were associated with lower levels of functional disability, through the mediation of fear and avoidance of pain. Relatedness satisfaction was not significatively related to fear of pain, avoidance, and functional disability. The integration of Self-Determination Theory in the paediatric pain literature may further our understanding of potential resources for decreasing functional disability in children living with chronic pain.

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How Should we Use Multicolumn Spinal Cord Stimulation to Optimize Back Pain Spatial Neural Targeting? A Prospective, Multicenter, Randomized, Double-Blind, Controlled Trial (ESTIMET Study).

Recent studies have highlighted multicolumn spinal cord stimulation (SCS) efficacy, hypothesizing that optimized spatial neural targeting provided by new-generation SCS lead design or its multicolumn programming abilities could represent an opportunity to better address chronic back pain (BP).

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Psoralens activate and photosensitize Transient Receptor Potential channels Ankyrin type 1 (TRPA1) and Vanilloid type 1 (TRPV1).

PUVA (psoralen UVA) therapy is used to treat a variety of skin conditions, such as vitiligo psoriasis, eczema and mycosis fungoides, but it is frequently accompanied by phototoxicity leading to burning pain, itch and erythema. Clinically used psoralen derivatives 8-methoxypsoralen (8-MOP) and 5-methoxypsoralen at physiologically relevant concentrations were able to activate and photosensitize two recombinant thermoTRP (temperature-gated Transient Receptor Potential) ion channels, TRPA1 (Transient Receptor Potential Ankyrin type 1) and TRPV1 (Transient Receptor Potential Vanilloid type 1), which are known to be involved in pain and itch signaling. 8-MOP enhanced reactive oxygen species (ROS) production by UVA light, and the effect of 8-MOP on TRPA1 could be abolished by the antioxidant N-acetyl cysteine and by removal of critical cysteine residues from the N-terminus domain of the channel. Natively expressed mouse TRPA1 and TRPV1 both contribute to photosensitization of cultured primary afferent neurons by 8-MOP, while direct neuronal activation by this psoralen-derivative is mainly dependent on TRPV1. Both TRPA1 and TRPV1 are to a large extent involved in controlling 8-MOP-induced neuropeptide release from mouse trachea. Taken together our results provide a better understanding of the phototoxicity reported by PUVA patients and indicate a possible therapeutic approach to alleviate the adverse effects associated with this therapy.

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Computational analysis of a 9D model for a small DRG neuron.

Small dorsal root ganglion (DRG) neurons are primary nociceptors which are responsible for sensing pain. Elucidation of their dynamics is essential for understanding and controlling pain. To this end, we present a numerical bifurcation analysis of a small DRG neuron model in this paper. The model is of Hodgkin-Huxley type and has 9 state variables. It consists of a Na1.7 and a Na1.8 sodium channel, a leak channel, a delayed rectifier potassium, and an A-type transient potassium channel. The dynamics of this model strongly depend on the maximal conductances of the voltage-gated ion channels and the external current, which can be adjusted experimentally. We show that the neuron dynamics are most sensitive to the Na1.8 channel maximal conductance ([Formula: see text]). Numerical bifurcation analysis shows that depending on [Formula: see text] and the external current, different parameter regions can be identified with stable steady states, periodic firing of action potentials, mixed-mode oscillations (MMOs), and bistability between stable steady states and stable periodic firing of action potentials. We illustrate and discuss the transitions between these different regimes. We further analyze the behavior of MMOs. As the external current is decreased, we find that MMOs appear after a cyclic limit point. Within this region, bifurcation analysis shows a sequence of isolated periodic solution branches with one large action potential and a number of small amplitude peaks per period. For decreasing external current, the number of small amplitude peaks is increasing and the distance between the large amplitude action potentials is growing, finally tending to infinity and thereby leading to a stable steady state. A closer inspection reveals more complex concatenated MMOs in between these periodic MMO branches, forming Farey sequences. Lastly, we also find small solution windows with aperiodic oscillations which seem to be chaotic. The dynamical patterns found here-as consequences of bifurcation points regulated by different parameters-have potential translational significance as repetitive firing of action potentials imply pain of some form and intensity; manipulating these patterns by regulating the different parameters could aid in investigating pain dynamics.

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Moderate or severe low back pain is associated with body mass index amongst community-dwelling older Australians.

Low back pain is prevalent in older populations and modifiable risk factors may include being overweight or obese. This study aimed to describe the prevalence and impact of moderate or severe low back pain in community-dwelling older adults and its association with body mass index (BMI).

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Exploring the underlying mechanism of pain-related disability in hypermobile adolescents with chronic musculoskeletal pain.

Objectives A significant proportion of adolescents with chronic musculoskeletal pain (CMP) experience difficulties in physical functioning, mood and social functioning, contributing to diminished quality of life. Generalized joint hypermobility (GJH) is a risk factor for developing CMP with a striking 35-48% of patients with CMP reporting GJH. In case GJH occurs with one or more musculoskeletal manifestations such as chronic pain, trauma, disturbed proprioception and joint instability, it is referred to as generalized hypermobility spectrum disorder (G-HSD). Similar characteristics have been reported in children and adolescents with the hypermobile Ehlers-Danlos Syndrome (hEDS). In the management of CMP, a biopsychosocial approach is recommended as several studies have confirmed the impact of psychosocial factors in the development and maintenance of CMP. The fear-avoidance model (FAM) is a cognitive-behavioural framework that describes the role of pain-related fear as a determinant of CMP-related disability. Content Pubmed was used to identify existing relevant literature focussing on chronic musculoskeletal pain, generalized joint hypermobility, pain-related fear and disability. Relevant articles were cross-referenced to identify articles possibly missed during the primary screening. In this paper the current state of scientific evidence is presented for each individual component of the FAM in hypermobile adolescents with and without CMP. Based on this overview, the FAM is proposed explaining a possible underlying mechanism in the relations between GJH, pain-related fear and disability. Summary and outlook It is assumed that GJH seems to make you more vulnerable for injury and experiencing more frequent musculoskeletal pain. But in addition, a vulnerability for heightened pain-related fear is proposed as an underlying mechanism explaining the relationship between GJH and disability. Further scientific confirmation of this applied FAM is warranted to further unravel the underlying mechanism. In explaining disability in individuals with G-HSD/hEDS, it is important to focus on both the physical components related to joint hypermobility, in tandem with the psychological components such as pain-related fear, catastrophizing thoughts and generalized anxiety.

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A Phenomenological Exploration of the Personal Implications of Female Adolescents Living With Chronic Pain.

Chronic pain (CP) negatively impacts everyday previously taken-for-granted activities resulting in considerable psychosocial stress for the individual. Qualitative research in pediatric CP is limited despite the considerable influence CP has on the process of establishing one's personal identity during these formative years and invites the opportunity to understand how CP affects these young individuals from their perspective. The objective of the study was to inquire into the experiences of female adolescents living with CP in order to enhance our understanding of how CP affects their personal lives.

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Clinical Relevance of Bladder Histopathological Findings and Their Impact on Treatment Outcomes Among Patients With Interstitial Cystitis/Bladder Pain Syndrome: An Investigation of the European Society for the Study of Interstitial Cystitis Histopathologi

The current study aimed to investigate the clinical significance of European Society for the Study of Interstitial Cystitis (ESSIC) bladder histopathological classification and its impact on treatment outcomes among patients with interstitial cystitis/bladder pain syndrome (IC/BPS).

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Role of CD14-positive cells in inflammatory cytokine and pain-related molecule expression in human degenerated intervertebral discs.

Multiple human and animal studies suggest that the up-regulation of inflammatory cytokines and other pain-related molecules in degenerated or injured intervertebral discs (IVDs) may cause discogenic low back pain (LBP). We previously reported that macrophages in injured IVD in mice produced inflammatory cytokines, but not other pain-related molecules. CD14 is a monocyte marker expressed mainly by macrophages. The aim of the current study was to evaluate the role of CD14-positive cells in inflammatory cytokine and pain-related molecule expression in human degenerated IVD. IVD samples were harvested from 14 patients, including 10 with lumbar spinal stenosis, 4 with adult spinal deformity, and 1 with lumbar disc herniation during spinal interbody fusion surgery. Harvested IVD-derived mononuclear cells were obtained and CD14-positive (+) and CD14-negative (-) cells were separated using CD14 antibody and streptavidin-labeled magnetic beads. Inflammatory cytokines mRNA in the CD14(+) and CD14(-) cells, including tumor necrosis factor alpha (TNFA), in,terleukin-1β (IL1B) and IL6, were determined using quantitative polymerase chain reaction(qPCR) and their expression levels were compared. To evaluate factors controlling the regulation of pain-related molecules mRNA expression, cultured CD14(-) and CD14(+) cells from IVDs were stimulated with recombinant human TNF-alpha and IL-1beta and levels of pain-related molecules, including calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) were determined using qPCR. Levels of TNFA, IL1B, IL6, and NGF in CD14(+) cells were significantly increased compared with those in CD14(-) cells (TNFA, p=0.006; IL1B, p=0.017; IL6, p=0.010; NGF, p=0.027). Following TNFA stimulation, NGF levels were significantly increased in CD14(-) and CD14(+) cells (CD14(-), p=0.003; CD14(+), p<0.001) and CGRP was significantly increased in CD14(-) IVD cells (p=0.040). Following IL1B stimulation, NGF levels were significantly increased in CD14(-) cells (p=0.004). CD14(+) cells had higher TNFA, IL1B, IL6, and NGF expressions than CD14(-) cells in human degenerated IVDs. Additionally, TNFA stimulation promoted the upregulation of NGF and CGRP in CD14(-) cells. These findings suggested that CD14(+) cells directly and indirectly contributed to inflammatory cytokine and pain-related molecule expression in human degenerated IVD. CD14(+) cells might be important in the pathological mechanism of chronic discogenic LBP in humans. This article is protected by copyright. All rights reserved.

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Biased versus Partial Agonism in the Search for Safer Opioid Analgesics.

Opioids such as morphine-acting at the mu opioid receptor-are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(-/-)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(-/-) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR-17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR-17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or 'apparent bias'. Overall, the current data suggests-and we support-caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.

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Role of Rho-associated coiled-coil containing protein kinase in the spinal cord injury induced neuropathic pain.

Spinal cord injury (SCI) can lead to increased phosphorylation of p38 in spinal cord microglia. This is one of the main causes for the development of persistent pain. Recently, we reported our study on the activation of p38 mitogen-activated protein kinases (MAPK) in spinal microglia, which has been considered the key molecule for the onset and maintenance of neuropathic pain after peripheral nerve injury, using a rat model. We also reported that the RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) pathway mediates p38 activation in spinal microglia in peripheral nerve injury. But the precise mechanisms of neuropathic pain induced by SCI are still unclear.

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Health-related quality of life in burning mouth syndrome – a case-control study.

Objectives The cardinal symptom of burning mouth syndrome (BMS) is long-lasting pain and comprehensive health-related quality of life (HRQL) assessments may estimate how well patients with BMS live in relation to their health issues. The aims of the study were to explore general and BMS-specific HRQL based on an HRQL model and to compare HRQL in patients with BMS and age-matched controls. Methods For this case-control study 56 female patients with BMS and 56 female controls completed the following: A general questionnaire with Global items for life satisfaction, general health and oral health; General Population-Clinical Outcomes in Routine Evaluation (GP-CORE); Hospital Anxiety and Depression Scale (HADS); and Oral Health Impact Profile-14 (OHIP-14). Patients with BMS completed additional questionnaires which included BMS-problem severity, a global item for ratings of overall severity perceptions measured by visual analog scale (VAS); and BMS-modified Multidimensional Pain Inventory-Swedish version (MPI-S). BMS-modified MPI-S includes the three subscales Pain severity, Interference and Social support. Results Patients with BMS scored worse on all global items, GP-CORE, HADS and OHIP-14 compared to controls and the differences were large. Patients with severe BMS problems, as defined by a median split on BMS-problem severity, scored worse on the BMS-modified MPI-S subscale Pain severity and the difference was large. Conclusions We found clearly impaired general HRQL in patients with BMS compared to controls. For specific HRQL, the severity of pain was worse among patients with higher overall BMS-problem severity. The HRQL model with global ratings together with physical, psychological and social concepts has capacity to increase comparability and validity of studies, however further evaluations of the measures are needed. The HRQL model may be used over time to increase the understanding of different HRQL aspects and their internal relationships. In clinical settings, with an increased knowledge of one´s own distinctive quality of life abilities and restrictions, the patients with BMS can be guided and supported to manage their long-lasting pain. The HRQL model may be an aid toward bridging distinctions between general and oral health to further encourage collaboration between medicine and odontology.

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Secreted Osteoclastogenic Factor of Activated T Cells (SOFAT) Is Associated With Rheumatoid Arthritis and Joint Pain: Initial Evidences of a New Pathway.

Rheumatoid arthritis (RA) has an inflammatory milieu in the synovial compartment, which is regulated by a complex cytokine and chemokine network that induces continuously degenerative and inflammatory reactions. The secreted osteoclastogenic factor of activated T cells (SOFAT) is a unique cytokine and represents an alternative pathway for osteoclast activation. In this study, we examined whether SOFAT is able to induce joint pain and investigated the presence of SOFAT in a Collagen-induced Arthritis (CIA) model and in human subjects. Here, we found that an intra-articular stimulation with SOFAT (1, 10, 100, or 1,000 ng/10 μl) in the knee joint significantly decreases the mechanical threshold in the hind paw of mice ( < 0.05). Moreover, after a second injection of SOFAT, the mechanical threshold decrease was sustained for up to 8 days ( < 0.05). In the CIA model, the immunohistochemical assay of knee joint showed positivity stained for SOFAT, and the mRNA and protein expression of SOFAT were significantly higher in the affected-group ( < 0.05). Besides, the mRNA of RANKL, IL-1β, IL-6, and IL-15 were significantly higher in the affected-group ( < 0.05). Finally, SOFAT was detected in the synovial fluid of RA patients, but not in OA patients ( < 0.05). In conclusion, SOFAT is up regulated in inflammatory milieu such as RA but not in non-inflammatory OA. SOFAT may be a novel molecule in the complex inflammatory phenotype of RA.

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