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Papers: 6 Mar 2021 - 12 Mar 2021

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Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain.

Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.

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Spinal macrophages resolve nociceptive hypersensitivity after peripheral injury.

Peripheral nerve injury induces long-term pro-inflammatory responses in spinal cord glial cells that facilitate neuropathic pain, but the identity of endogenous cells that resolve spinal inflammation has not been determined. Guided by single-cell RNA sequencing (scRNA-seq), we found that MRC1 spinal cord macrophages proliferated and upregulated the anti-inflammatory mediator Cd163 in mice following superficial injury (SI; nerve intact), but this response was blunted in nerve-injured animals. Depleting spinal macrophages in SI animals promoted microgliosis and caused mechanical hypersensitivity to persist. Conversely, expressing Cd163 in spinal macrophages increased Interleukin 10 expression, attenuated micro- and astrogliosis, and enduringly alleviated mechanical and thermal hypersensitivity in nerve-injured animals. Our data indicate that MRC1 spinal macrophages actively restrain glia to limit neuroinflammation and resolve mechanical pain following a superficial injury. Moreover, we show that spinal macrophages from nerve-injured animals mount a dampened anti-inflammatory response but can be therapeutically coaxed to promote long-lasting recovery of neuropathic pain.

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Silent cold-sensing neurons contribute to cold allodynia in neuropathic pain.

Neuropathic pain patients often experience innocuous cooling as excruciating pain. The cell and molecular basis of this cold allodynia is little understood. We used in vivo calcium imaging of sensory ganglia to investigate how the activity of peripheral cold-sensing neurons was altered in three mouse models of neuropathic pain: Oxaliplatin-induced neuropathy, partial sciatic nerve ligation and ciguatera poisoning. In control mice, cold-sensing neurons were few in number and small in size. In neuropathic animals with cold allodynia, a set of normally silent large-diameter neurons became sensitive to cooling. Many of these silent cold-sensing neurons responded to noxious mechanical stimuli and expressed the nociceptor markers NaV1.8 and CGRPα. Ablating neurons expressing NaV1.8 resulted in diminished cold allodynia. The silent cold-sensing neurons could also be activated by cooling in control mice through blockade of KV1 voltage-gated potassium channels. Thus silent cold-sensing neurons are unmasked in diverse neuropathic pain states and cold allodynia results from peripheral sensitization caused by altered nociceptor excitability.

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Emerging role of RNA m6A modification in chronic pain.

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Long-lasting analgesia via targeted in situ repression of Na1.7 in mice.

Current treatments for chronic pain rely largely on opioids despite their substantial side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in Na1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between Na subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of Na1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Toward this end, we first optimized the efficiency of Na1.7 repression in vitro in Neuro2A cells and then, by the lumbar intrathecal route, delivered both epigenome engineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain, and BzATP-induced pain. Our results show effective repression of Na1.7 in lumbar dorsal root ganglia, reduced thermal hyperalgesia in the inflammatory state, decreased tactile allodynia in the neuropathic state, and no changes in normal motor function in mice. We anticipate that this long-lasting analgesia via targeted in vivo epigenetic repression of Na1.7 methodology we dub pain LATER, might have therapeutic potential in management of persistent pain states.

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Distinct thalamocortical circuits underlie allodynia induced by tissue injury and by depression-like states.

In humans, tissue injury and depression can both cause pain hypersensitivity, but whether this involves distinct circuits remains unknown. Here, we identify two discrete glutamatergic neuronal circuits in male mice: a projection from the posterior thalamic nucleus (PO) to primary somatosensory cortex glutamatergic neurons (S1) mediates allodynia from tissue injury, whereas a pathway from the parafascicular thalamic nucleus (PF) to anterior cingulate cortex GABA-containing neurons to glutamatergic neurons (ACC) mediates allodynia associated with a depression-like state. In vivo calcium imaging and multi-tetrode electrophysiological recordings reveal that PO and PF populations undergo different adaptations in the two conditions. Artificial manipulation of each circuit affects allodynia resulting from either tissue injury or depression-like states, but not both. Our study demonstrates that the distinct thalamocortical circuits PO→S1 and PF→ACC subserve allodynia associated with tissue injury and depression-like states, respectively, thus providing insights into the circuit basis of pathological pain resulting from different etiologies.

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Gender biases in estimation of others’ pain.

Caregiving and other interpersonal interactions often require accurate perception of others' pain from nonverbal cues, but perceivers may be subject to systematic biases based on gender, race, and other contextual factors. Such biases could contribute to systematic under-recognition and under-treatment of pain. In two experiments, we studied the impact of perceived patient sex on lay perceivers' pain estimates and treatment recommendations. In Experiment 1 (N = 50), perceivers viewed facial video clips of female and male patients in chronic shoulder pain and estimated patients' pain intensity. Multi-level linear modeling revealed that perceivers under-estimated female patients' pain compared with male patients, after controlling for patients' self-reported pain and pain facial expressiveness. Experiment 2 (N = 200) replicated these findings, and additionally found that 1) perceivers' pain-related gender stereotypes, specifically beliefs about typical women's vs. men's willingness to express pain, predicted pain estimation biases; and 2) perceivers judged female patients as relatively more likely to benefit from psychotherapy, whereas male patients were judged to benefit more from pain medicine. In both experiments, the gender bias effect size was on average 2.45 points on a 0-100 pain scale. Gender biases in pain estimation may be an obstacle to effective pain care, and experimental approaches to characterizing biases, such as the one we tested here, could inform the development of interventions to reduce such biases. PERSPECTIVE: This study identifies a bias towards underestimation of pain in female patients, which is related to gender stereotypes. The findings suggest caregivers' or even clinicians' pain stereotypes are a potential target for intervention.

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Fibromyalgia versus small fiber neuropathy: diverse keratinocyte transcriptome signature.

Damage to thinly-myelinated and unmyelinated nerve fibers causes small fiber pathology, which is increasingly found in pain syndromes such as small fiber neuropathy (SFN) and fibromyalgia syndrome (FMS). The peripheral nerve endings of the small nerve fibers terminate within the epidermis, where they are surrounded by keratinocytes that may act as primary nociceptive transducers.We performed RNA sequencing of keratinocytes obtained from patients with SFN, FMS, and healthy controls. We found 141 deregulated protein coding genes between SFN patients and healthy controls and no differentially expressed genes between FMS patients and healthy controls. When comparing SFN with FMS patients, we detected 167 differentially expressed protein coding genes (129 upregulated, 38 downregulated). Further analysis revealed enriched inflammatory pathways. Validation of selected candidates in an independent cohort confirmed higher expression of the pro-inflammatory mediators interleukin-8, C-X-C motif chemokine 3, endothelin receptor type A, and the voltage-gated sodium channel 1.7 in SFN compared to FMS patients.We provide a diverse keratinocyte transcriptome signature between SFN and FMS patients, which may hint towards distinct pathomechanisms of small fiber sensitization in both entities and lay the basis for advanced diagnostics.

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When Eating Becomes a Pain in the Gut.

Irritable bowel syndrome often appears following gastrointestinal infection and is marked by diarrhea, dysbiosis, fever, and intestinal pain following eating. A recent study by Aguilera-Lizarraga et al. now demonstrates that a breakdown in intestinal immunotolerance sparks an inflammatory response to typically tolerated food antigens and causes visceral pain.

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Cross-sectional study on sex differences in chronic pain patients using the DATAPAIN cohort.

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Pain is not the major determinant of quality of life in fibromyalgia: results from a retrospective “real world” data analysis of fibromyalgia patients.

To identify correlates of quality of life (QoL) measured with the Quality of Life Scale (QOLS) in participants of a multidisciplinary day hospital treatment program for fibromyalgia (FM).

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The Psychological Functioning in the COVID-19 Pandemic and Its Association with Psychological Flexibility and Broader Functioning in People with Chronic Pain.

People with chronic pain may be particularly vulnerable to the impact of the pandemic COVID-19, and psychological flexibility may protect them. This study investigates psychological functioning in the context of COVID-19, including fear and avoidance in the context of COVID-19, specifically its association with daily functioning, and the role of psychological flexibility, among people with chronic pain.

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P2X4R contributes to central disinhibition via TNF-α/TNFR1/GABAaR pathway in post-stroke pain rats.

Central post-stroke pain (CPSP) is a disabling condition in stroke patients. It is a type of neuropathic pain for which the mechanism and relevant drug pathways remain unknown. Inflammatory response and central disinhibition have been suggested recently. Our previous research has shown targeting P2X4R may be effective in the treatment of CPSP, but the downstream pathway of the P2X4R has not been studied. In this study, we found the increase in TNF-α level and endocytosis of surface GABAaR in CPSP, and these effects were inhibited by blocking P2X4R. Furthermore, antagonizing TNF-α can increase surface GABAaR expression and mechanical pain threshold. Meanwhile, knocking down TNFR1 but not TNFR2 reversed the endocytosis of surface GABAaR and alleviated mechanical allodynia. Thus, the neuropathic pain was mediated, in part, through P2X4R/TNF-α/TNFR1/GABAaR signaling, which was induced after stroke. PERSPECTIVE: P2X4R regulates the pathophysiological mechanism of CPSP through central disinhibition mediated by TNF-α/TNFR1. Our results suggest that modulation of P2X4R-TNF-α/TNFR1-GABAaR signaling could provide a new therapeutic strategy to treat CPSP.

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Medial Prefrontal High-Definition Transcranial Direct Current Stimulation to Improve Pain Modulation in Chronic Low Back Pain: A Pilot Randomized Double-blinded Placebo-Controlled Crossover Trial.

Chronic low back pain (CLBP) is highly disabling, but often without identifiable source. Focus has been on impaired anti-nociceptive mechanisms contributing to pain maintenance, though methods of targeting this impairment remain limited. This randomised-controlled cross-over pilot trial used active versus sham medial prefrontal cortex (mPFC) high-definition transcranial direct current stimulation (HD-tDCS) for three-consecutive days to improve descending pain inhibitory function. Twelve CLBP patients were included with an average visual analogue scale (VAS) pain intensity of 3.0±1.5 and pain duration of 5.3±2.6 years. Pressure pain thresholds (PPTs), conditioned pain modulation (CPM), and temporal summation of pain (TSP) assessed by cuff algometry, as well as pain symptomatology (intensity, unpleasantness, quality, disability) and related psychological features (pain catastrophizing, anxiety, affect), were assessed on Day1 before three consecutive days of HD-tDCS sessions (each 20 min), at 24-hours (Day4) and 2-weeks (Day21) following final HD-tDCS. Blinding was successful. No significant differences in psychophysical (PPT, CPM, TSP), symptomatology or psychological outcomes were observed between active and sham HD-tDCS on Day4 and Day21. CPM-effects at Day1 negatively correlated with change in CPM-effect at Day4 following active HD-tDCS (P=0.002). Lack of efficacy was attributed to several factors, not least that patients did not display impaired CPM at baseline. TRIAL REGISTRATION: : ClinicalTrials.gov (NCT03864822) PERSPECTIVE: Medial prefrontal HD-tDCS did not alter pain, psychological nor psychophysical outcomes, though correlational analysis suggested response may depend on baseline pain inhibitory efficacy, with best potential effects in patients with severe impairments in descending pain inhibitory mechanisms. Future work should focus on appropriate patient selection and optimising stimulation targeting.

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Patient and Provider Acceptability of a Patient Preauthorized Concealed Opioid Reduction.

Limited research of how to best taper opioids brings about an ethical and clinical dilemma. Experiments using overt and concealed administration of opioids have demonstrated the benefits of a concealed reduction to eliminate negative expectations and prolong analgesic benefits. This may allow for opioid tapering without significant increases in pain. Based on this, we investigated patient and provider acceptance of a concealed opioid reduction for chronic pain.

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Medial Prefrontal Transcranial Direct Current Stimulation Aimed to Improve Affective and Attentional Modulation of Pain in Chronic Low Back Pain Patients.

Chronic low back pain (CLBP) is often without clear underlying pathology. Affective disturbance and dysfunctional pain mechanisms, commonly observed in populations with CLBP, have, therefore, been suggested as potential contributors to CLBP development and maintenance. However, little consensus exists on how these features interact and if they can be targeted using non-invasive brain stimulation. In this pilot trial, 12 participants completed two phases (Active or Sham) of high-definition transcranial direct current stimulation (HD-tDCS) to the medial prefrontal cortex, applied for 20 min on three consecutive days. Clinical pain ratings, questionnaires, and sensitivity to painful cuff pressure were completed at baseline, then 4 trials of conditioned pain modulation (CPM; alone, with distraction using a Flanker task, with positive affect induction, and with negative affect induction using an image slideshow) were performed prior to HD-tDCS on Day 1 and Day 4 (24 h post-HD-tDCS). At baseline, attentional and affective manipulations were effective in inducing the desired state ( < 0.001) but did not significantly change the magnitude of CPM-effect. Active HD-tDCS was unable to significantly alter the magnitude of the shift in valence and arousal due to affective manipulations, nor did it alter the magnitude of CPM under any basal, attentional, or affective manipulation trial significantly on Day 4 compared to sham. The CPM-effect was greater across all manipulations on Day 1 than Day 4 ( < 0.02) but also showed poor reliability across days. Future work is needed to expand upon these findings and better understand how and if HD-tDCS can be used to enhance attentional and affective effects on pain modulation.

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Using Mediation Analysis to Understand How Treatments for Paediatric Pain Work: A Systematic Review and Recommendations for Future Research.

Clinicians have an increasing number of evidence-based interventions to treat pain in youth. Mediation analysis offers a way of investigating how interventions work, by examining the extent to which an intermediate variable, or mediator, explains the effect of an intervention. This systematic review examined studies that used mediation analysis to investigate mechanisms of interventions on pain-relevant outcomes for youth (3-18 years) with acute or chronic pain, and provides recommendations for future mediation research in this field. We searched five electronic databases for clinical trials or observational longitudinal studies that included a comparison group and conducted mediation analyses of interventions on youth and assessed pain outcomes. We found six studies ( = 635), which included a total of 53 mediation models examining how interventions affect pain-relevant outcomes for youth. Five studies were secondary analyses of randomized controlled trials of psychological interventions for chronic pain; one was a longitudinal observational study of morphine for acute pain. The pain conditions studied were irritable bowel syndrome, functional abdominal pain, juvenile fibromyalgia, mixed chronic pain, and post-operative pain. Fourteen putative mediators were tested, of which three partially mediated treatment effect; seven did not significantly mediate treatment effect and four had mixed results. Methodological and reporting limitations were common. There are substantial gaps in the field with respect to investigating, and therefore understanding, how paediatric interventions work.

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Effects of inflammatory pain on CB1 receptor in the midbrain periaqueductal gray.

The periaqueductal gray (PAG) mediates the antinociceptive properties of analgesics, including opioids and cannabinoids. Administration of either opioids or cannabinoids into the PAG induces antinociception. However, most studies characterizing the antinociceptive properties of cannabinoids in the PAG have been conducted in naive animals. Few studies have reported on the role of CB1 receptors in the PAG during conditions which would prompt the administration of analgesics, namely, during pain states.

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Role of Peripheral Immune Cells for Development and Recovery of Chronic Pain.

Chronic neuropathic pain (CNP) is caused by a lesion or disease of the somatosensory nervous system. It affects ~8% of the general population and negatively impacts a person's level of functioning and quality of life. Its resistance to available pain therapies makes CNP a major unmet medical need. Immune cells have been shown to play a role for development, maintenance and recovery of CNP and therefore are attractive targets for novel pain therapies. In particular, in neuropathic mice and humans, microglia are activated in the dorsal horn and peripheral immune cells infiltrate the nervous system to promote chronic neuroinflammation and contribute to the initiation and progression of CNP. Importantly, immunity not only controls pain development and maintenance, but is also essential for pain resolution. In particular, regulatory T cells, a subpopulation of T lymphocytes with immune regulatory function, and macrophages were shown to be important contributors to pain recovery. In this review we summarize the interactions of the peripheral immune system with the nervous system and outline their contribution to the development and recovery of pain.

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Prolonged time of after-sensation after experimental pain stimuli despite efficient conditioned pain modulation in patients with chronic neuropathic pain after traumatic nerve injuries in upper extremity.

As yet, there is limited research that can identify factors that differentiate between painful and nonpainful neuropathies after traumatic nerve injury. The aim of this study was to compare subjects with pain and without pain, all after operative nerve repair in the upper extremities.

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Genome-wide association study identifies candidate loci associated with chronic pain and postherpetic neuralgia.

Human twin studies and other studies have indicated that chronic pain has heritability that ranges from 30% to 70%. We aimed to identify potential genetic variants that contribute to the susceptibility to chronic pain and efficacy of administered drugs. We conducted genome-wide association studies (GWASs) using whole-genome genotyping arrays with more than 700,000 markers in 191 chronic pain patients and a subgroup of 89 patients with postherpetic neuralgia (PHN) in addition to 282 healthy control subjects in several genetic models, followed by additional gene-based and gene-set analyses of the same phenotypes. We also performed a GWAS for the efficacy of drugs for the treatment of pain.

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Spa therapy for the treatment of fibromyalgia: an open, randomized multicenter trial.

Fibromyalgia is a common chronic pain pathology with an incidence of 4.3 per 1000 person-years. An open, randomized clinical trial of patients with fibromyalgia comparing an immediate vs. delayed 18-day spa therapy in five spa therapy care facilities in France enrolled 220 patients. Randomization was in blocks of four, stratified by center, severity of fibromyalgia and previous spa therapy. Patients continued usual treatment. The main endpoint was the number of patients achieving minimal clinically important difference (MCID) at 6 months, defined as 14% change in their baseline fibromyalgia impact questionnaire (FIQ) score. The intention-to-treat analysis included 100 and 106 patients in the intervention and control groups, respectively. At 6 months, 45/100 (45.0%) and 30/106 (28.3%) patients in the intervention and control groups, respectively, achieved a MCID (p=0.013). There was also a significant improvement in pain, fatigue, and symptom severity (secondary outcomes) in the intervention group but not for generic quality of life (QOL), sleep or physical activity. None of the 33 serious adverse events reported by 25 patients were related to the spa therapy. Our results demonstrate the benefit of spa treatment in patients with fibromyalgia. PERSPECTIVE: A 12-month, open, randomized clinical trial of 220 patients with fibromyalgia compared an immediate vs. delayed (i.e. after 6 months) 18-day spa therapy. The results showed a clinically significant improvement at 6 months for those who received immediate therapy which was maintained up to 12 months. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT02265029.

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Are sensory neurons exquisitely sensitive to interleukin 1β?

Peripheral nerve injury frequently evokes chronic neuropathic pain. This is initiated by a transient inflammatory response that leads to persistent excitation of dorsal root ganglion (DRG) neurons by inflammatory cytokines such as interleukin 1β(IL-1β). In non-neuronal cells such as lymphocytes, interleukin 1 exerts actions at attomolar (aM; 10 M) concentrations. We now report that DRG neurons in defined-medium, neuron-enriched culture display increased excitability following 5-6 d exposure of 1aM IL-1β. This response is mediated in part by type 1 interleukin receptors and involves decreased function of putative K1.1 channels. This finding provides new insights into the neuroimmune interactions responsible for neuropathic pain.

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Mind-body approaches targeting the psychological aspects of opioid use problems in patients with chronic pain: Evidence and opportunities.

Opioids are commonly prescribed for the management of patients with chronic noncancer pain. Despite the potential analgesic benefits of opioids, long-term opioid therapy (LTOT) may be accompanied by problems such as opioid misuse and opioid use disorder (OUD). In this review, we begin with a description of opioid misuse and OUD and the patient-specific factors associated with these problems among patients with chronic pain. We will focus primarily on highlighting the predominant role played by psychological factors in the occurrence of opioid misuse and OUD in these patients. Several psychological factors have been found to be associated with opioid use problems in patients with chronic pain, and evidence indicates that patients presenting with psychological disturbances are particularly at risk of transitioning to long-term opioid use, engaging in opioid misuse behaviors, and developing OUD. The biological factors that might underlie the association between psychological disturbances and opioid use problems in patients with chronic pain have yet to be fully elucidated, but a growing number of studies suggest that dysfunctions in reward, appetitive, autonomic, and neurocognitive systems might be involved. We end with an overview of specific types of psychological interventions that have been put forward to prevent or reduce the occurrence of opioid misuse and OUD in patients with chronic pain who are prescribed long-term opioid therapy.

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Pharmacological Modulation of Rate-Dependent Depression of the Spinal H-Reflex Predicts Therapeutic Efficacy against Painful Diabetic Neuropathy.

Impaired rate-dependent depression (RDD) of the spinal H-reflex occurs in diabetic rodents and a sub-set of patients with painful diabetic neuropathy. RDD is unaffected in animal models of painful neuropathy associated with peripheral pain mechanisms and diabetic patients with painless neuropathy, suggesting RDD could serve as a biomarker for individuals in whom spinal disinhibition contributes to painful neuropathy and help identify therapies that target impaired spinal inhibitory function. The spinal pharmacology of RDD was investigated in normal rats and rats after 4 and 8 weeks of streptozotocin-induced diabetes. In normal rats, dependence of RDD on spinal GABAergic inhibitory function encompassed both GABA and GABA receptor sub-types. The time-dependent emergence of impaired RDD in diabetic rats was preceded by depletion of potassium-chloride co-transporter 2 (KCC2) protein in the dorsal, but not ventral, spinal cord and by dysfunction of GABA receptor-mediated inhibition. GABA receptor-mediated spinal inhibition remained functional and initially compensated for loss of GABA receptor-mediated inhibition. Administration of the GABA receptor agonist baclofen restored RDD and alleviated indices of neuropathic pain in diabetic rats, as did spinal delivery of the carbonic anhydrase inhibitor acetazolamide. Pharmacological manipulation of RDD can be used to identify potential therapies that act against neuropathic pain arising from spinal disinhibition.

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Subcutaneous ω-Conotoxins Alleviate Mechanical Pain in Rodent Models of Acute Peripheral Neuropathy.

The peripheral effects of ω-conotoxins, selective blockers of N-type voltage-gated calcium channels (Ca2.2), have not been characterised across different clinically relevant pain models. This study examines the effects of locally administered ω-conotoxin MVIIA, GVIA, and CVIF on mechanical and thermal paw withdrawal threshold (PWT) in postsurgical pain (PSP), cisplatin-induced neuropathy (CisIPN), and oxaliplatin-induced neuropathy (OIPN) rodent models. Intraplantar injection of 300, 100 and 30 nM MVIIA significantly ( < 0.0001, < 0.0001, and < 0.05, respectively) alleviated mechanical allodynia of mice in PSP model compared to vehicle control group. Similarly, intraplantar injection of 300, 100, and 30 nM MVIIA ( < 0.0001, < 0.01, and < 0.05, respectively), and 300 nM and 100 nM GVIA ( < 0.0001 and < 0.05, respectively) significantly increased mechanical thresholds of mice in OIPN model. The ED of GVIA and MVIIA in OIPN was found to be 1.8 pmol/paw and 0.8 pmol/paw, respectively. However, none of the ω-conotoxins were effective in a mouse model of CisIPN. The intraplantar administration of 300 nM GVIA, MVIIA, and CVIF did not cause any locomotor side effects. The intraplantar administration of MVIIA can alleviate incision-induced mechanical allodynia, and GVIA and MVIIA effectively reduce OIPN associated mechanical pain, without locomotor side effects, in rodent models. In contrast, CVIF was inactive in these pain models, suggesting it is unable to block a subset of N-type voltage-gated calcium channels associated with nociceptors in the skin.

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Leveraging VR/AR to combat chronic pain in youth: Position paper from the Interdisciplinary Network on Virtual and Augmented (AR/VR) Technologies for Pain (INOVATE-Pain) Management.

Virtual reality (VR) and augmented reality (AR) interventions are emerging as promising tools in the treatment of pediatric chronic pain conditions, but in this young field there is little consensus to guide the process of engaging in the development and evaluation of targeted VR-based interventions.

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DUSP1 Promotes Microglial Polarization toward M2 Phenotype in the Medial Prefrontal Cortex of Neuropathic Pain Rats via Inhibition of MAPK Pathway.

Shifting microglial polarization from M1 toward M2 phenotype represents a promising therapeutic strategy for neuropathic pain (NP). Dual-specificity phosphatase-1 (DUSP1) is a key component in regulating anti-inflammatory response. The medial prefrontal cortex (mPFC) is implicated in emotional disorders associated with NP and constitutes a neuroanatomical substrate for exploring mechanisms underlying NP. This study aims to investigate whether DUSP1 regulates microglial M1/M2 polarization in the mPFC in a rat model of NP. Rat model of NP was established by chronic constriction injury (CCI) of the rat sciatic nerve. Lipopolysaccharide (LPS) was used to activate HAPI rat microglial cells as an inflammatory model. CCI-induced decreased pain threshold, increased cell apoptosis in mPFC, elevated pro-inflammatory M1/M2 microglia ratio, and activated MAPK signaling in the mPFC of rats. Importantly, intra-mPFC injection of DUSP1-expressing lentivirus counteracted these abnormalities. assay further confirmed that DUSP1 overexpression switched microglial M1 to M2 polarization through inhibition of MAPK signaling activation. DUSP1 switched microglial M1 to M2 polarization in the mPFC and attenuated CCI-induced NP by inhibiting the MAPK signaling.

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Minimally Invasive Oral Surgery Induction of the FRICT-ION Chronic Neuropathic Pain Model.

An easily induced preclinical trigeminal neuropathic nerve injury model is described here for the study of chronic pain, the model acronym oramen otundum nflammatory onstriction rigeminal nfrarbital erve). In patients, neuropathic pain is thought to be related to vascular alignment or multiple sclerosis along this small trigeminal nerve branch (V2) innervating the maxillary teeth and middle third of the face. With no detectable outward physical signs, the FRICT-ION model is ideal for blinded studies. The acronym FRICT-ION applied relates to the persistence of the trigeminal neuropathic pain model likely due to sliding irritation with normal chewing in the mice. A step-by-step method to induce the mild chronic rodent neuropathic pain model is described here. The surgery is performed orally through a tiny surgical slit inside the cheek crease to align a chromic gut suture irritant along the nerve as it passes into the skull. The model allows testing of non-evoked subjective measures and evoked quantitative mechanical hypersensitivity (allodynia) testing with von Frey filaments through at least 10-14 weeks (100 days). Anxiety and depression behaviors develop within 3-6 weeks relevant to the affective component of chronic pain. While many pain drugs have failed based on testing performed in the acute animal models available, the more stable and easily replicated trigeminal inflammatory compression model is the better suited for understanding both mechanistic and affective components of nerve injury-induced chronic neuropathic pain states as well as the more ideal for preclinical trials of novel non-opioid pain relief therapies.

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Nonpharmacological Interventions for Pediatric Migraine: A Network Meta-analysis.

Migraine is a common neurologic disorder in children and adolescents. However, a comparison of multiple nonpharmacological treatments is lacking.

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Confirmatory factor analysis of the International Pain Outcome questionnaire in surgery.

Choosing perioperative suitable treatments requires reliable and valid outcome measurements. The International Pain Outcome (IPO) questionnaire has been widely used for quality improvement and research purposes within the PAIN-OUT network that has collected more than 550,000 data sets of postoperative patients in 200 hospitals worldwide. Our aim is to confirm psychometric properties of the Spanish version of the IPO questionnaire and its invariance by pain predictors.

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Preoperative Sleep Quality And Adverse Pain Outcomes After Total Hip Arthroplasty.

Sleep disturbance is thought to aggravate acute postoperative pain. The influence of preoperative sleep problems on pain control in the long-term and development of chronic postsurgical pain is largely unknown.

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The challenges of precision medicine in chronic low back pain: Lessons learned from active discopathy.

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A new synthetic protectin D1 analog 3-oxa-PD1 reduces neuropathic pain and chronic itch in mice.

The resolution of inflammation is a biosynthetically active process controlled by the interplay between oxygenated polyunsaturated mediators and G-protein coupled receptor-signaling pathways. These enzymatically oxygenated polyunsaturated fatty acids belong to distinct families of specialized pro-resolving autacoids. The protectin family of mediators has attracted an interest because of their potent pro-resolving and anti-inflammatory actions verified in several in vivo disease models. Herein, we present the stereoselective synthesis and biological evaluations of 3-oxa-PD1n-3 DPA, a protectin D1 analog. Results from mouse models indicate that the mediators protectin D1, PD1n-3 DPA and the new analog 3-oxa-PD1n-3 DPA all relieved streptozotocin-induced diabetic neuropathic pain at doses of 90 and 300 pmol, equivalent to 30 and 100 ng, respectively, following intrathecal (I.T.) injection. Of interest, at a low dose of only 30 pmol (10 ng; I.T.) only 3-oxa PD1n-3 DPA was able to alleviate neuropathic pain, directly compared to vehicle controls. Moreover, using a chronic itch model of cutaneous T-cell lymphoma (CTCL), all three compounds at 300 pmol (100 ng) showed a significant reduction in itching for several hours. The biomolecular information on the structure-functions of the protectins and the new synthetic analog 3-oxa-PD1n-3 DPA is of interest towards developing new immunoresolvents.

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High Genetic Addiction Risk Score (GARS) in Chronically Prescribed Severe Chronic Opioid Probands Attending Multi-pain Clinics: an Open Clinical Pilot Trial.

Millions of Americans experience pain daily. In 2017, opioid overdose claimed 64,000 lives increasing to 84,000 lives in 2020, resulting in a decrease in national life expectancy. Chronic opioid use results in dependency, drug tolerance, neuroadaptation, hyperalgesia, potential addictive behaviors, or Reward Deficiency Syndrome (RDS) caused by a hypodopaminergia. Evaluation of pain clinic patients with the Genetic Addiction Risk Score (GARS) test and the Addiction Severity Index (ASI- Media Version V) revealed that GARS scores equal to or greater than 4 and 7 alleles significantly predicted drug and alcohol severity, respectively. We utilized RT-PCR for SNP genotyping and multiplex PCR/capillary electrophoresis for fragment analysis of the role of eleven alleles in a ten-reward gene panel, reflecting the activity of brain reward circuitry in 121 chronic opioid users. The study consisted of 55 males and 66 females averaging ages 54 and 53 years of age, respectively. The patients included Caucasians, African Americans, Hispanics, and Asians. Inclusion criteria mandated that the Morphine Milligram Equivalent (MME) was 30-600 mg/day (males) and 20 to 180 mg/day (females) for treatment of chronic pain over 12 months. Ninety-six percent carried four or more risk alleles, and 73% carried seven or more risk alleles, suggesting a high predictive risk for opioid and alcohol dependence, respectively. These data indicate that chronic, legally prescribed opioid users attending a pain clinic possess high genetic risk for drug and alcohol addiction. Early identification of genetic risk, using the GARS test upon entry to treatment, may prevent iatrogenic induced opioid dependence.

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Minimal clinically important differences in randomised clinical trials on pain management after total hip and knee arthroplasty: a systematic review.

Sample size determination is essential for reliable hypothesis testing in clinical trials and should rely on adequate sample size calculations with alpha, beta, variance, and an effect size being the minimal clinically important difference (MCID). This facilitates interpretation of the clinical relevance of statistically significant results. No gold standard for MCIDs exists in postoperative pain research.

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Neurokinin 1 Receptor Antagonists for Pruritus.

Pruritus, commonly known as itch, is a very common symptom in numerous dermatological disorders and systemic diseases. It can manifest as acute, or when lasting longer than 6 weeks, it is considered chronic and can lead to significant distress and reduced quality-of-life of those suffering. Current therapeutics are limited and are lacking in efficacy, and the development of more effective treatments is needed. The neurokinin 1 receptor (NK1R) antagonists are a novel class of drugs that possess several properties such as antidepressant, anxiolytic and antiemetic activities. Recently, several studies have described the antipruritic activity of NK1R antagonists for treating chronic pruritus. In this review we outline the pathogenesis of chronic pruritus, the mechanism by which the neuropeptide substance P (SP) and its receptor NK1R may be targeted to inhibit pruritic activity, and the efficacy and tolerability of NK1R antagonists, which have been, or are currently being investigated for treating conditions where chronic pruritus is a major symptom. Increasing evidence from ongoing and completed studies demonstrates the importance of SP and NK1R signalling in mediating pruritic activity. Several NK1R antagonists have shown significant antipruritic activity and thus targeting the SP-NK1R pathway may provide a therapeutic option for treating chronic pruritus of certain origin/s in the foreseeable future.

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Characterization of acute pain-induced behavioral passivity in mice: insights from statistical modeling.

Affective-motivational disturbances are highly inconsistent in animal pain models. The reproducibility of the open-field test in assessing anxiety, malaise, or disability remains controversial despite its popularity. While traumatic, persistent, or multi-regional pain models are commonly considered more effective in inducing negative affect or functional impairment, the early psychobehavioral changes before pain chronification are often underexplored. Here, we aimed to clarify the fundamental relationship between hypernociception and passive distress-like behavior using a model of transient inflammatory pain. To minimize latent confounders and increase data consistency, male C57BL/6N mice were habituated to the open-field arena 6 times before receiving the unilateral intraplantar injection of prostaglandin E2 (PGE2) or vehicle. Open-field (40-minute exploration) and nociceptive behavior were evaluated repeatedly along the course of hypernociception in both wild-type and transgenic mice with a known pronociceptive phenotype. To reduce subjectivity, multivariate open-field behavioral outcomes were analyzed by statistical modeling based on exploratory factor analyses, which yielded a 2-factor solution. Within 3 hours after PGE2 injection, mice developed significantly reduced center exploration (factor 1) and a marginally significant increase in their habituation tendency (factor 2), which were not apparent in vehicle-injected mice. The behavioral passivity generally improved as hypernociception subsided. Therefore, transient inflammatory irritation is sufficient to suppress mouse open-field exploratory activity. The apparent absence of late affective-motivational changes in some rodents with prolonged hypernociception may not imply a lack of preceding or underlying neuropsychological alterations. Procedural pain after invasive animal experiments, however small, should be assessed and adequately controlled as a potential research confounder.

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Intrinsic burst-firing in lamina I spinoparabrachial neurons during adolescence.

A subset of glutamatergic interneurons in the neonatal spinal superficial dorsal horn (SDH) exhibits intrinsic burst-firing (i.e. 'pacemaker' activity), which is tightly regulated by persistent, voltage-gated Na channels and classic inward-rectifying K (K2) channels and downregulated over the course of postnatal development. Ascending lamina I projection neurons targeting the parabrachial nucleus (PB) or periaqueductal gray (PAG) can also display pacemaker activity during early life. However, the degree to which the ionic mechanisms driving pacemaker activity are conserved across different cell types in the spinal dorsal horn, as well as whether the intrinsic bursting is restricted to newborn projection neurons, remains to be elucidated. Using in vitro patch clamp recordings from identified lamina I spinoparabrachial neurons in rat spinal cord slices, here we demonstrate that adolescent projection neurons retain their ability to generate pacemaker activity. In contrast to previous findings in lamina I interneurons, pacemaker projection neurons possessed higher membrane capacitance, lower membrane resistance, and a greater density of K-mediated conductance compared to adjacent spinoparabrachial neurons that lacked intrinsic burst-firing. Nonetheless, as previously seen in interneurons, the bath application of riluzole to block persistent Na channels significantly dampened pacemaker activity in projection neurons. Collectively, these results suggest that intrinsic burst-firing in the developing dorsal horn can be generated by multiple combinations of ionic conductances, and highlight the need for further investigation into the mechanisms governing pacemaker activity within the major output neurons of the SDH network.

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Perineural high-mobility group box 1 induces mechanical hypersensitivity through activation of spinal microglia: involvement of glutamate-NMDA receptor dependent mechanism in spinal dorsal horn.

High mobility box 1 (HMGB1), a damage-associated molecular pattern, has crucial roles in induction of neuropathic pain. Upregulation of HMGB1 around the injured sciatic nerve contributes to mechanical hypersensitivity following partial sciatic nerve ligation (PSNL) of mice. However, central mechanisms mediating perineural HMGB1-induced nociceptive hypersensitivity, especially within the spinal dorsal horn, have not been determined. The current study shows that perineural treatment of naïve mice with recombinant HMGB1, which mimics increased HMGB1 around the injured sciatic nerve of PSNL mice, significantly induced activation of microglia, but not astrocytes, in the spinal dorsal horn. Intraperitoneal injection of minocycline, a microglial inhibitor, ameliorated perineural rHMGB1-induced mechanical hypersensitivity. In addition, blockade of spinal N-methyl-D-aspartate (NMDA) receptors significantly prevented perineural rHMGB1-induced mechanical hypersensitivity and microglial activation. In contrast, non-NMDA receptors, neurokinin 1 receptor, colony-stimulating factor 1 receptor and P2Y12 receptor were not involved in perineural rHMGB1-induced mechanical hypersensitivity. Furthermore, repeated perineural treatment with an anti-HMGB1 antibody blocked activation of spinal microglia in PSNL mice. Collectively, the current findings demonstrate that increased HMGB1 around injured sciatic nerve might induce nociceptive hypersensitivity through activation of spinal microglia. Thus, HMGB1-dependent mechanisms between the injured sciatic nerve and spinal dorsal horn could be crucial in induction of neuropathic pain.

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A Network Analysis of Clinical Variables in Chronic Pain: A Study from the Swedish Quality Registry for Pain Rehabilitation (SQRP).

Efforts to identify specific variables that impact most on outcomes from interdisciplinary pain rehabilitation are challenged by the complexity of chronic pain. Methods to manage this complexity are needed. The purpose of the study was to determine the network structure entailed in a set of self-reported variables, examine change, and look at potential predictors of outcome, from a network perspective.

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TRAF6 Contributes to CFA-Induced Spinal Microglial Activation and Chronic Inflammatory Pain in Mice.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) has been reported to be expressed in spinal astrocytes and is involved in neuropathic pain. In this study, we investigated the role and mechanism of TRAF6 in complete Freund's adjuvant (CFA)-evoked chronic inflammatory hypersensitivity and the effect of docosahexaenoic acid (DHA) on TRAF6 expression and inflammatory pain. We found that TRAF6 was dominantly increased in microglia at the spinal level after intraplantar injection of CFA. Intrathecal TRAF6 siRNA alleviated CFA-triggered allodynia and reversed the upregulation of IBA-1 (microglia marker). In addition, intrathecal administration of DHA inhibited CFA-induced upregulation of TRAF6 and IBA-1 in the spinal cord and attenuated CFA-evoked mechanical allodynia. Furthermore, DHA prevented lipopolysaccharide (LPS)-caused increase of TRAF6 and IBA-1 in both BV2 cell line and primary cultured microglia. Finally, intrathecal DHA reduced LPS-induced upregulation of spinal TRAF6 and IBA-1, and alleviated LPS-induced mechanical allodynia. Our findings indicate that TRAF6 contributes to pain hypersensitivity via regulating microglial activation in the spinal dorsal horn. Direct inhibition of TRAF6 by siRNA or indirect inhibition by DHA may have therapeutic effects on chronic inflammatory pain.

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I don’t identify with it”: A qualitative analysis of people’s experiences of living with Complex Regional Pain Syndrome.

Complex Regional Pain Syndrome (CRPS) is a painful limb condition known to cause significant disability and distress. However, little previous research has explored CRPS from a patient perspective. The present qualitative study aimed to describe the experiences of people living with CRPS.

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Assessment of pain modulatory and somatosensory profiles in chronic tension-type headache patients.

The aim of this study was to thoroughly phenotype a group of chronic tension-type headache (CTTH) patients.

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New Insight into the Origins of Itch and Pain: How are Itch and Pain Signals Coded and Discriminated by Primary Sensory Neurons?

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Evaluation of Posttraumatic Headache Phenotype and Recovery Time After Youth Concussion.

The Four Corners Youth Consortium was created to fill the gap in our understanding of youth concussion. This study is the first analysis of posttraumatic headache (PTH) phenotype and prognosis in this cohort of concussed youth.

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Efficacy and Tolerability of Calcitonin Gene-Related Peptide Targeted Monoclonal Antibody Medications as Add-on Therapy to OnabotulinumtoxinA in Patients with Chronic Migraine.

We examined the efficacy and tolerability of calcitonin gene-related peptide targeted monoclonal antibodies (CGRP-targeted mAbs) as add-on therapy for patients with chronic migraine (CM) undergoing treatment with onabotulinumtoxinA(onabot) who require additional preventive therapy.

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Dorsal root ganglia NR2B-mediated Epac1-Piezo2 signaling pathway contributes to mechanical allodynia of bone cancer pain.

Mechanical allodynia is a painful perception of mechanical stimuli and one of the typical symptoms in bone cancer pain (BCP). Previous studies have revealed that mice and humans lacking mechanically activated Piezo2 channels do not sense mechanical stimuli. However, the underlying mechanism of Piezo2 in BCP has not been well established. The aim of the present study was to investigate whether exchange protein directly activated by cAMP 1 (Epac1) mediated Piezo2 signaling pathway may be responsible for the mechanical allodynia of BCP and whether N-methyl-D-aspartic acid (NMDA) receptor subunit 2B (NR2B) is involved in the pathway. In the present study, a BCP model was established in C3H/HeJ mice by intramedullary injection of osteosarcoma cells. The results of the mechanical allodynia test demonstrated a markedly decreased paw withdrawal mechanical threshold in BCP mice, accompanied by a significant increase in Epac1, NR2B proteins and Piezo2 mRNA expression levels in the ipsilateral dorsal root ganglion (DRG). Compared with the sham group, intrathecal Epac1 antisense oligodeoxynucleotides (Epac1-ASODN) effectively ameliorated the mechanical allodynia and decreased the expression levels of NR2B and Piezo2 in the tumor group. Pretreatment of naïve mice with a NR2B antagonist prevented the aggravation of mechanical allodynia and DRG Piezo2 levels induced by an Epac1 agonist. However, the NR2B agonist-induced increase in Piezo2 expression levels was not reversed by pretreatment with Epac1-ASODN. In conclusion, the results of the present study demonstrated that NR2B, which is a crucial downstream regulator of Epac1, may mediate the Epac1-Piezo2 pathway contributing to the development of the mechanical allodynia of BCP. The present study may enrich the theoretical knowledge of the mechanical allodynia of BCP and provide a potential analgesic strategy for clinical treatment.

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Relationship between Post-Traumatic Stress Disorder Symptoms and Chronic Pain Related Symptom Domains among Military Active Duty Service Members.

This study examined the relationships between symptom domains relevant to PTSD diagnosis, PTSD screening, and chronic pain-related symptoms (pain intensity, pain interference, physical function, fatigue, depression, anxiety, anger, satisfaction with social roles) experienced by active duty military service members with chronic pain.

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The Relationship Between Androgens and Days per Month of Period Pain, Pelvic Pain, Headache, and TLR4 Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhoea.

Women bear a disproportionate burden of persistent pain conditions when compared to men. To determine whether the hormonal environment affects the clinical experience of pain, as measured by the days per month of pelvic pain (DPelvicPM), period pain (DPeriodPM), headache (DHeadachePM) or the in vitro EC for Interleukin-1β (IL-1β) release following TLR4 stimulation with Lipopolysaccharide from Peripheral Blood Mononuclear Cells (PBMCs). Findings were stratified according to use or non-use of the oral contraceptive pill.

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Using a machine learning approach to investigate factors associated with treatment-resistant depression among adults with chronic non-cancer pain conditions and major depressive disorder.

Presence of chronic non-cancer pain conditions (CNPC) among adults with major depressive disorder (MDD) may reduce benefits of antidepressant therapy, thereby increasing the possibility of treatment resistance. This study sought to investigate factors associated with treatment-resistant depression (TRD) among adults with MDD and CNPC using machine learning approaches.

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Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers.

The kynurenine pathway (KP) is the main path for tryptophan metabolism, and it represents a multitude of potential sites for drug discovery in neuroscience, including pain, stroke, and epilepsy. L-kynurenine (LKYN), the first active metabolite in the pathway, emerges to be a prodrug targeting glutamate receptors. The safety, tolerability, pharmacokinetics, and pharmacodynamics of LKYN in humans have not been previously investigated. In an open-label, single ascending dose study, six participants received an intravenous infusion of 50, 100, and 150 µg/kg LKYN and new six participants received an intravenous infusion of 0.3, 0.5, 1, and 5 mg/kg LKYN. To compare the pharmacological effects between species, we investigated in vivo the vascular effects of LKYN in rats. In humans, LKYN was safe and well-tolerated at all dose levels examined. After infusion, LKYN plasma concentration increased significantly over time 3.23 ± 1.12 µg/mL (after 50 µg/kg), 4.04 ± 1.1 µg/mL (after 100 µg/kg), and 5.25 ± 1.01 µg/mL (after 150 µg/kg) (p ≤ 0.001). We observed no vascular changes after infusion compared with baseline. In rats, LKYN had no effect on HR and MAP and caused no dilation of dural and pial arteries. This first-in-human study of LKYN showed that LKYN was safe and well-tolerated after intravenous infusion up to 5 mg/kg over 20 minutes. The lack of change in LKYN metabolites in plasma suggests a relatively slow metabolism of LKYN and no or little feed-back effect of LKYN on its synthesis. The therapeutic potential of LKYN in stroke and epilepsy should be explored in future studies in humans.

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Feasibility of patient-focused behavioral interventions to support adults experiencing chronic noncancer pain during opioid tapering: a systematic literature review.

Guidelines for chronic noncancer pain prioritize behavioral treatments. In clinical practice transition from opioids to behavioral treatments is often not endorsed by patients or providers. Feasible interventions to support opioid tapering are needed, particularly in primary care. The objectives of this paper is to review the feasibility of behavioral interventions to support opioid tapering. Electronic databases (MEDLINE, Embase, PsycINFO, and CINAHL) were searched from inception to June 2019 to identify original studies reporting feasibility (consent rates; completion rates; patient-reported acceptability; integration into clinical practice; and adverse events) of opioid tapering and transition to behavioral treatments for adults experiencing chronic noncancer pain. Google scholar and contents tables of key journals were also searched. Two authors independently extracted data and assessed methodological quality using The Quality Assessment Tool for Quantitative Studies. Eleven publications met inclusion criteria, of which three were conducted in primary care. Consent rates ranged from 27% to 98% and completion rates from 6.6% to 100%. Four studies rated at least one component of patient acceptability: helpfulness from 50%-81%; satisfaction 71%-94%, and "recommend to others" 74%-91%. Three studies reported provider perspectives and two studies reported adverse events. Quality assessment indicated all 11 studies were moderate or weak, primarily due to selection bias and lack of assessor blinding. There was also considerable heterogeneity in study design. The limited available data suggest that attempts to translate opioid tapering interventions into practice are likely to encounter substantial feasibility challenges. One possible way to ameliorate this challenge may be a clear policy context, which facilitates and support opioid reduction.

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Different dosage regimens of Eptinezumab for the treatment of migraine: a meta-analysis from randomized controlled trials.

Migraine is one of the most common neurological diseases around the world and calcitonin gene-related peptide (CGRP) plays an important role in its pathophysiology. Therefore, in the present study, we evaluated the efficacy of monoclonal antibodies blocking the CGRP ligand or receptor in episodic and chronic migraine.

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Post-traumatic Headache and Mild Traumatic Brain Injury: Brain Networks and Connectivity.

Post-traumatic headache (PTH) consequent to mild traumatic brain injury (mTBI) is a complex, multidimensional, chronic neurological disorder. The purpose of this review is to evaluate the current neuroimaging studies on mTBI and PTH with a specific focus on brain networks and connectivity patterns.

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Psychiatric comorbidity and order of condition onset among patients seeking treatment for chronic pain and opioid use disorder.

The study objective was to compare psychiatric comorbidity among patients seeking treatment for chronic pain and opioid use disorder (OUD) by order of condition onset (i.e., "Pain First," "OUD First," "Same Time").

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Perceived social support in patients with chronic pain with and without opioid use disorder and role of medication for opioid use disorder.

A significant predictor of treatment outcomes for patients with chronic non-cancer pain (CNCP) and opioid use disorder (OUD) is the degree and quality of social support they receive. Specifically, in patients with CNCP and on long-term opioid therapy, the development of OUD tends to be associated with losses in social support, while engagement in treatment for OUD improves support networks. Delivery of the evidence-based OUD treatment medications, methadone and buprenorphine, occurs in clinical environments which patently differ with respect to social support resources. The aims of this study were to describe perceived social support in patients with CNCP without OUD (no-OUD), with OUD and on buprenorphine (OUD-BP), and with OUD and on methadone (OUD-methadone).

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TRPV1 Activation Promotes β-arrestin2 Interaction with the Ribosomal Biogenesis Machinery in the Nucleolus:Implications for p53 Regulation and Neurite Outgrowth.

Transient receptor potential vanilloids TRPV1) are non-selective cation channels that sense and transduce inflammatory pain signals. We previously reported that activation of TRPV1 induced the translocation of β-arrestin2 (ARRB2) from the cytoplasm to the nucleus, raising questions about the functional role of ARRB2 in the nucleus. Here, we determined the ARRB2 nuclear signalosome by conducting a quantitative proteomic analysis of the nucleus-sequestered L395Q ARRB2 mutant, compared to the cytosolic wild-type ARRB2 (WT ARRB2), in a heterologous expression system. We identified clusters of proteins that localize to the nucleolus and are involved in ribosomal biogenesis. Accordingly, L395Q ARRB2 or WT ARRB2 after capsaicin treatment were found to co-localize and interact with the nucleolar marker nucleophosmin (NPM1), treacle protein (TCOF1) and RNA polymerase I (POL I). We further investigated the role of nuclear ARRB2 signaling in regulating neuroplasticity. Using neuroblastoma (neuro2a) cells and dorsal root ganglia (DRG) neurons, we found that L395Q ARRB2 mutant increased POL I activity, inhibited the tumor suppressorp53 (p53) level and caused a decrease in the outgrowth of neurites. Together, our results suggest that the activation of TRPV1 promotes the ARRB2-mediated regulation of ribosomal biogenesis in the nucleolus. The ARRB2-TCOF1-p53 checkpoint signaling pathway might be involved in regulating neurite outgrowth associated with pathological pain conditions.

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Larger pain extent is associated with greater pain intensity and disability but not with general health status or psychosocial features in patients with cervical radiculopathy.

Pain as a result of cervical radiculopathy (CR) can be widespread, nondermatomal and individually specific, but the association between pain extent and other clinical features has never been explored. The objective of this study is to investigate whether pain extent relates to clinical variables including pain intensity in addition to health indicators including disability, general health, depression, somatic anxiety, coping strategies or self-efficacy.An observational cohort study was conducted. Participants were recruited from 4 hospital spinal centres in Sweden. Pain extent was quantified from the pain drawings of 190 individuals with cervical disc disease, verified with magnetic resonance imaging (MRI) and compatible with clinical findings (examined by a neurosurgeon), that show cervical nerve root compression. Pain extent was evaluated in relation to neck pain, arm pain, and headache intensity. Multiple linear regression analysis were then used to verify whether pain extent was associated with other health indicators including disability, health-related quality of life, depression, somatic anxiety, coping strategies and self-efficacy.Pain extent was directly related to neck, arm and headache pain intensity (all P < .01). Multiple linear regression revealed that pain extent was significantly associated only to the level of perceived disability (P < .01).Increased pain extent in people with CR is associated with higher headache, neck and arm pain intensity, and disability but not measures of general health, depression, somatic anxiety, coping strategies or self-efficacy.

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