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Papers: 24 Oct 2020 - 30 Oct 2020

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Association of Therapies With Reduced Pain and Improved Quality of Life in Patients With Fibromyalgia: A Systematic Review and Meta-analysis.

Fibromyalgia is a chronic condition that results in a significant burden to individuals and society.

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Pain in long-term survivors of childhood cancer: A systematic review of the current state of knowledge and a call to action from the Children’s Oncology Group.

Survivors of childhood cancer may be at risk of experiencing pain, and a systematic review would advance our understanding of pain in this population. The objective of this study was to describe: 1) the prevalence of pain in survivors of childhood cancer, 2) methods of pain measurement, 3) associations between pain and biopsychosocial factors, and 4) recommendations for future research. Data sources for the study were articles published from January 1990 to August 2019 identified in the PubMed, PsycINFO, EMBASE, and Web of Science data bases. Eligible studies included: 1) original research, 2) quantitative assessments of pain, 3) articles published in English, 4) cancers diagnosed between birth and age 21 years, 5) survivors at 5 years from diagnosis and/or at 2 years after therapy completion, and 6) a sample size >20. Seventy-three articles were included in the final review. Risk of bias was considered using the Cochrane risk of bias tool. The quality of evidence was evaluated according to Grading of Recommendations Assessment Development and Evaluation (GRADE) criteria. Common measures of pain were items created by the authors for the purpose of the study (45.2%) or health-related quality-of-life/health status questionnaires (42.5%). Pain was present in from 4.3% to 75% of survivors across studies. Three studies investigated chronic pain according the definition in the International Classification of Diseases. The findings indicated that survivors of childhood cancer are at higher risk of experiencing pain compared with controls. Fatigue was consistently associated with pain, females reported more pain than males, and other factors related to pain will require stronger evidence. Theoretically grounded, multidimensional measurements of pain are absent from the literature.

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Status of peripheral sodium channel blockers for non-addictive pain treatment.

The effective and safe treatment of pain is an unmet health-care need. Current medications used for pain management are often only partially effective, carry dose-limiting adverse effects and are potentially addictive, highlighting the need for improved therapeutic agents. Most common pain conditions originate in the periphery, where dorsal root ganglion and trigeminal ganglion neurons feed pain information into the CNS. Voltage-gated sodium (Na) channels drive neuronal excitability and three subtypes – Na1.7, Na1.8 and Na1.9 – are preferentially expressed in the peripheral nervous system, suggesting that their inhibition might treat pain while avoiding central and cardiac adverse effects. Genetic and functional studies of human pain disorders have identified Na1.7, Na1.8 and Na1.9 as mediators of pain and validated them as targets for pain treatment. Consequently, multiple Na1.7-specific and Na1.8-specific blockers have undergone clinical trials, with others in preclinical development, and the targeting of Na1.9, although hampered by technical constraints, might also be moving ahead. In this Review, we summarize the clinical and preclinical literature describing compounds that target peripheral Na channels and discuss the challenges and future prospects for the field. Although the potential of peripheral Na channel inhibition for the treatment of pain has yet to be realized, this remains a promising strategy to achieve non-addictive analgesia for multiple pain conditions.

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Substance P Release by Sensory Neurons Triggers Dendritic Cell Migration and Initiates the Type-2 Immune Response to Allergens.

Dendritic cells (DCs) of the cDC2 lineage initiate allergic immunity and in the dermis are marked by their expression of CD301b. CD301b dermal DCs respond to allergens encountered in vivo, but not in vitro. This suggests that another cell in the dermis may sense allergens and relay that information to activate and induce the migration of CD301b DCs to the draining lymph node (dLN). Using a model of cutaneous allergen exposure, we show that allergens directly activated TRPV1 sensory neurons leading to itch and pain behaviors. Allergen-activated sensory neurons released the neuropeptide Substance P, which stimulated proximally located CD301b DCs through the Mas-related G-protein coupled receptor member A1 (MRGPRA1). Substance P induced CD301b DC migration to the dLN where they initiated T helper-2 cell differentiation. Thus, sensory neurons act as primary sensors of allergens, linking exposure to activation of allergic-skewing DCs and the initiation of an allergic immune response.

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Towards the endotyping of the sleep-pain interaction: a topical review on multitarget strategies based on phenotypic vulnerabilities and putative pathways.

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Symptom appraisal in uncertainty: a theory-driven thematic analysis with survivors of childhood cancer.

Somatic symptoms capture attention, demand interpretation, and promote health behaviors. Symptom appraisal is particularly impactful within uncertain health contexts such as cancer survivorship. Yet, little is known about how individuals make sense of somatic symptoms within uncertain health contexts, nor how this process guides health behaviors.

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Altered trigeminal pain processing on brainstem level in persistent idiopathic facial pain.

Persistent Idiopathic Facial Pain (PIFP) is a poorly understood chronic pain syndrome of the face, formerly known as atypical facial pain. It is characterized by a constant painful sensation without neurological abnormalities and without clinically objectifiable cause. Similarities to neuropathic pain conditions have been discussed and are currently thought to be relevant for the pathophysiology of this disease. In this study we aim to characterize the trigeminal pain processing in PIFP via functional magnetic resonance imaging (fMRI) of the brainstem.25 patients suffering from PIFP and 25 healthy controls (HC) underwent a standardized and well-established paradigm of painful stimulation of the trigeminal nerve using gaseous ammonia. Functional images were acquired within a 3T MRI scanner using an optimized protocol for high resolution echoplanar brainstem imaging.PIFP patients show exclusively a stronger activation to painful stimulation in the spinal trigeminal nucleus (sTN) when contrasted against HC.Our data suggest that abnormal central pain processing plays a role in the pathophysiology of PIFP. An integration of these findings into neuropathic pain models might help to gain a better general understanding of the pathophysiology of PIFP.

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Ubiquitin-mediated receptor degradation contributes to development of tolerance to MrgC agonist-induced pain inhibition in neuropathic rats.

Agonists to subtype C of the Mas-related G-protein-coupled receptors (MrgC) induce pain inhibition after intrathecal (i.t.) administration in rodent models of nerve injury. Here, we investigated whether tolerance develops after repeated MrgC agonist treatments and examined the underlying mechanisms. In animal behavior studies conducted in male rats at 4-5 weeks after an L5 spinal nerve ligation (SNL), the ability of dipeptide MrgC agonist JHU58 (0.1 mM, 10 μL, i.t.) to inhibit mechanical and heat hypersensitivity decreased after 3 days of treatment with a tolerance-inducing dose (0.5 mM, 10 μL, i.t., twice/day). In HEK293T cells, acute treatment with JHU58 or BAM8-22 (a large peptide MrgC agonist) led to MrgC endocytosis from the cell membrane, and later sorting to the membrane for reinsertion. However, chronic exposure to JHU58 increased the coupling of MrgC to β-arrestin-2 and led to the ubiquitination and degradation of MrgC. Importantly, pretreatment with TAK-243 (0.2 mM, 5 μL, i.t.), a small-molecule inhibitor of the ubiquitin activating enzyme, during tolerance induction attenuated the development of tolerance to JHU58-induced inhibition of mechanical and heat hypersensitivity in SNL rats. Interestingly, morphine analgesia was also decreased in SNL rats that had become tolerant to JHU58, suggesting a cross-tolerance. Furthermore, intrathecal pretreatment with TAK-243, which reduced JHU58 tolerance, also attenuated the cross-tolerance to morphine analgesia. These findings suggest that tolerance can develop to MrgC agonist-induced pain inhibition after repeated intrathecal administrations. This tolerance development to JHU58 may involve increased coupling of MrgC to β-arrestin-2 and ubiquitin-mediated receptor degradation.

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Effect of Electroacupuncture vs Sham Treatment on Change in Pain Severity Among Adults With Chronic Low Back Pain: A Randomized Clinical Trial.

Chronic low back pain has high societal and personal impact but remains challenging to treat. Electroacupuncture has demonstrated superior analgesia compared with placebo in animal studies but has not been extensively studied in human chronic pain conditions.

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Are you in pain if you say you are not? Accounts of pain in Somali-Canadian women with female genital cutting (FGC).

As a rite of passage to womanhood, 2 million girls undergo female genital circumcision (FGC) – the tradition of cutting, and often removing parts of the vulva – every year. The current study is the first to focus on the connection between peripheral nerve damage and chronic neuropathic pain in women with FGC. We used mixed methods – quantitative, qualitative and physiological – to study chronic pain in Somali-Canadian women (N = 14). These women have the most extensive form of FGC, which includes removal of the glans clitoris, labia minora, medial portion of the labia majora, and stitching together the remaining parts of the labia majora. Our results indicate a multifaceted pain experience in women with FGC. Although they report good overall health and very low pain levels on the short form of the McGill Pain Questionnaire, pressure-pain quantitative sensory testing of the vulvar region applied through vulvalgesiometers shows pain thresholds consistent with those reported by women with chronic vulvar pain. Furthermore, qualitative interviews reveal a considerable amount of often debilitating pain in daily life. These results challenge the use of assessment tools offering elicited verbal pain language and highlight the importance of culturally sensitive ways of conceptualizing, measuring and managing pain.

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Multidisciplinary research priorities for the COVID-19 pandemic: a call for action for mental health science.

The coronavirus disease 2019 (COVID-19) pandemic is having a profound effect on all aspects of society, including mental health and physical health. We explore the psychological, social, and neuroscientific effects of COVID-19 and set out the immediate priorities and longer-term strategies for mental health science research. These priorities were informed by surveys of the public and an expert panel convened by the UK Academy of Medical Sciences and the mental health research charity, MQ: Transforming Mental Health, in the first weeks of the pandemic in the UK in March, 2020. We urge UK research funding agencies to work with researchers, people with lived experience, and others to establish a high level coordination group to ensure that these research priorities are addressed, and to allow new ones to be identified over time. The need to maintain high-quality research standards is imperative. International collaboration and a global perspective will be beneficial. An immediate priority is collecting high-quality data on the mental health effects of the COVID-19 pandemic across the whole population and vulnerable groups, and on brain function, cognition, and mental health of patients with COVID-19. There is an urgent need for research to address how mental health consequences for vulnerable groups can be mitigated under pandemic conditions, and on the impact of repeated media consumption and health messaging around COVID-19. Discovery, evaluation, and refinement of mechanistically driven interventions to address the psychological, social, and neuroscientific aspects of the pandemic are required. Rising to this challenge will require integration across disciplines and sectors, and should be done together with people with lived experience. New funding will be required to meet these priorities, and it can be efficiently leveraged by the UK's world-leading infrastructure. This Position Paper provides a strategy that may be both adapted for, and integrated with, research efforts in other countries.

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The input-output relation of primary nociceptive neurons is determined by the morphology of the peripheral nociceptive terminals.

The output from the peripheral terminals of primary nociceptive neurons, which detect and encode the information regarding noxious stimuli, is crucial in determining pain sensation. The nociceptive terminal endings are morphologically complex structures assembled from multiple branches of different geometry, which converge in a variety of forms to create the terminal tree. The output of a single terminal is defined by the properties of the transducer channels producing the generation potentials and voltage-gated channels, translating the generation potentials into action potential firing. However, in the majority of cases, noxious stimuli activate multiple terminals; thus, the output of the nociceptive neuron is defined by the integration and computation of the inputs of the individual terminals. Here we used a computational model of nociceptive terminal tree to study how the architecture of the terminal tree affects the input-output relation of the primary nociceptive neurons. We show that the input-output properties of the nociceptive neurons depend on the length, the axial resistance, and location of individual terminals. Moreover, we show that activation of multiple terminals by a capsaicin-like current allows summation of the responses from individual terminals, thus leading to increased nociceptive output. Stimulation of the terminals in simulated models of inflammatory or nociceptive hyperexcitability led to a change in the temporal pattern of action potential firing, emphasizing the role of temporal code in conveying key information about changes in nociceptive output in pathological conditions, leading to pain hypersensitivity.Noxious stimuli are detected by terminal endings of primary nociceptive neurons, which are organized into morphologically complex terminal trees. The information from multiple terminals is integrated along the terminal tree, computing the neuronal output, which propagates towards the CNS, thus shaping the pain sensation. Here we revealed that the structure of the nociceptive terminal tree determines the output of nociceptive neurons. We show that the integration of noxious information depends on the morphology of the terminal trees and how this integration and, consequently, the neuronal output change under pathological conditions. Our findings help to predict how nociceptive neurons encode noxious stimuli and how this encoding changes in pathological conditions, leading to pain.

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Toward Understanding Movement-evoked Pain (MEP) and its Measurement: A Scoping Review.

Individuals with chronic pain conditions often report movement as exacerbating pain. An increasing number of researchers and clinicians have recognized the importance of measuring and distinguishing between movement-evoked pain (MEP) and pain at rest as an outcome. This scoping review maps the literature and describes MEP measurement techniques.

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Magnetic Resonance Spectroscopy Assessment of Brain Metabolite Concentrations in Individuals with Chronic Whiplash Associated Disorder: A Cross-sectional Study.

Pathophysiologic mechanisms underpinning ongoing pain in whiplash associated disorder (WAD) are not well understood, however alterations in brain morphology and function have been observed in this population, as well as in other chronic pain conditions. This study investigated metabolite profiles of brain regions in people with chronic WAD compared with controls.

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Multisensory Sensitivity is Related to Deep-Tissue but Not Cutaneous Pain Sensitivity in Healthy Individuals.

Some individuals with chronic pain find daily life sensations (eg, noise, light, or touch) aversive. This amplification of multisensory sensations has been associated with centrally mediated plasticity; for example, greater multisensory sensitivity (MSS) occurs in patients with fibromyalgia than rheumatoid arthritis. However, whether MSS preferentially relates to pain measures which reflect central influences (eg, dynamic quantitative sensory testing (QST) or referred pain), or whether the MSS-pain relationship requires priming from chronic pain, is unknown. Thus, this cross-sectional study investigated the relationships between MSS assessed in a pain-free state and evoked pain sensitivity.

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Repeated Injections of Low-Dose Nerve Growth Factor (NGF) in Healthy Humans Maintain Muscle Pain and Facilitate Ischemic Contraction-Evoked Pain.

Nerve growth factor (NGF) is essential for generating and potentiating pain responses. This double-blinded crossover study assessed NGF-evoked pain in healthy humans after repeated NGF injections in the tibialis anterior (TA) muscle compared with control injections of isotonic saline.

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Diabetic Polyneuropathy Is Associated With Pathomorphological Changes in Human Dorsal Root Ganglia: A Study Using 3T MR Neurography.

Diabetic neuropathy (DPN) is one of the most severe and yet most poorly understood complications of diabetes mellitus. imaging of dorsal root ganglia (DRG), a key structure for the understanding of DPN, has been restricted to animal studies. These have shown a correlation of decreased DRG volume with neuropathic symptom severity. Our objective was to investigate correlations of DRG morphology and signal characteristics at 3 Tesla (3T) magnetic resonance neurography (MRN) with clinical and serological data in diabetic patients with and without DPN. In this cross-sectional study, participants underwent 3T MRN of both L5 DRG using an isotropic 3D T2-weighted, fat-suppressed sequence with subsequent segmentation of DRG volume and analysis of normalized signal properties. Overall, 55 diabetes patients (66 ± 9 years; 32 men; 30 with DPN) took part in this study. DRG volume was smaller in patients with severe DPN when compared to patients with mild or moderate DPN (134.7 ± 21.86 vs 170.1 ± 49.22; = 0.040). In DPN patients, DRG volume was negatively correlated with the neuropathy disability score ( = -0.43; 95%CI = -0.66 to -0.14; = 0.02), a measure of neuropathy severity. DRG volume showed negative correlations with triglycerides ( = -0.40; 95%CI = -0.57 to -0.19; = 0.006), and LDL cholesterol ( = -0.33; 95%CI = -0.51 to -0.11; = 0.04). There was a strong positive correlation of normalized MR signal intensity (SI) with the neuropathy symptom score in the subgroup of patients with painful DPN ( = 0.80; 95%CI = 0.46 to 0.93; = 0.005). DRG SI was positively correlated with HbA1c levels ( = 0.30; 95%CI = 0.09 to 0.50; = 0.03) and the triglyceride/HDL ratio ( = 0.40; 95%CI = 0.19 to 0.57; = 0.007). In this first study, we found DRG morphological degeneration and signal increase in correlation with neuropathy severity. This elucidates the potential importance of MR-based DRG assessments in studying structural and functional changes in DPN.

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K+ Channels in Primary Afferents and Their Role in Nerve Injury-Induced Pain.

Sensory abnormalities generated by nerve injury, peripheral neuropathy or disease are often expressed as neuropathic pain. This type of pain is frequently resistant to therapeutic intervention and may be intractable. Numerous studies have revealed the importance of enduring increases in primary afferent excitability and persistent spontaneous activity in the onset and maintenance of peripherally induced neuropathic pain. Some of this activity results from modulation, increased activity and /or expression of voltage-gated Na channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. K channels expressed in dorsal root ganglia (DRG) include delayed rectifiers (K1.1, 1.2), A-channels (K1.4, 3.3, 3.4, 4.1, 4.2, and 4.3), KCNQ or M-channels (K7.2, 7.3, 7.4, and 7.5), ATP-sensitive channels (K6.2), Ca-activated K channels (K1.1, 2.1, 2.2, 2.3, and 3.1), Na-activated K channels (K4.1 and 4.2) and two pore domain leak channels (K; TWIK related channels). Function of all K channel types is reduced via a multiplicity of processes leading to altered expression and/or post-translational modification. This also increases excitability of DRG cell bodies and nociceptive free nerve endings, alters axonal conduction and increases neurotransmitter release from primary afferent terminals in the spinal dorsal horn. Correlation of these cellular changes with behavioral studies provides almost indisputable evidence for K channel dysfunction in the onset and maintenance of neuropathic pain. This idea is underlined by the observation that selective impairment of just one subtype of DRG K channel can produce signs of pain Whilst it is established that various mediators, including cytokines and growth factors bring about injury-induced changes in DRG function and excitability, evidence presently available points to a seminal role for interleukin 1β (IL-1β) in control of K channel function. Despite the current state of knowledge, attempts to target K channels for therapeutic pain management have met with limited success. This situation may change with the advent of personalized medicine. Identification of specific sensory abnormalities and genetic profiling of individual patients may predict therapeutic benefit of K channel activators.

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Pain in Youth with Sickle Cell Disease: A Report from the Sickle Cell Clinical Research and Intervention Program.

Pain is prevalent among youth with sickle cell disease (SCD). However, previous research has been limited by small sample sizes, and lacked examinations of developmental differences in pain – which are critical to minimizing the development of chronic pain as youth transition into adulthood. The primary aim of the current study was to compare pain and pain interference across four developmental groups in a large sample of youth with SCD. The secondary aim was to identify risk factors for greater pain and pain interference.

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Sphingosine-1-phosphate receptor subtype 1 activation in the central nervous system contributes to morphine withdrawal in rodents.

Opioid therapies for chronic pain are undermined by many adverse side effects that reduce their efficacy and lead to dependence, abuse, reduced quality of life, and even death. We have recently reported that sphingosine-1-phosphate (S1P) 1 receptor (S1PR1) antagonists block the development of morphine-induced hyperalgesia and analgesic tolerance. However, the impact of S1PR1 antagonists on other undesirable side effects of opioids, such as opioid-induced dependence, remains unknown. Here, we demonstrate that naloxone-precipitated morphine withdrawal in mice altered de novo sphingolipid metabolism in the dorsal horn of the spinal cord and increased S1P that accompanied the manifestation of several withdrawal behaviors. Blocking de novo sphingolipid metabolism with intrathecal administration of myriocin, an inhibitor of serine palmitoyltransferase, blocked naloxone-precipitated withdrawal. Noteworthy, we found that competitive (NIBR-15) and functional (FTY720) S1PR1 antagonists attenuated withdrawal behaviors in mice. Mechanistically, at the level of the spinal cord, naloxone-precipitated withdrawal was associated with increased glial activity and formation of the potent inflammatory/neuroexcitatory cytokine interleukin-1β (IL-1β); these events were attenuated by S1PR1 antagonists. These results provide the first molecular insight for the role of the S1P/S1PR1 axis during opioid withdrawal. Our data identify S1PR1 antagonists as potential therapeutics to mitigate opioid-induced dependence and support repurposing the S1PR1 functional antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.

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Establishing Central Sensitization-Related Symptom Severity Subgroups: A Multicountry Study Using the Central Sensitization Inventory.

The goal of this study was to identify central sensitization-related symptom severity subgroups in a large multicountry sample composed of patients with chronic pain and pain-free individuals using the Central Sensitization Inventory (CSI).

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Dual-Acting Peripherally Restricted Delta/Kappa Opioid (CAV1001) Produces Antinociception in Animal Models of Sub-Acute and Chronic Pain.

The development of highly efficacious alternatives to mu-opioid analgesics represents an urgent unmet medical and public health need. In the presence of inflammation both delta- and kappa-opioid agonists, acting on peripheral sensory neurons, mediate analgesia. The dual-acting, peripherally restricted kappa/delta-opioid agonist, CAV1001, was tested in four rodent pain models.

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Cytokine activin C ameliorates chronic neuropathic pain in peripheral nerve injury rodents by modulating the TRPV1 channel.

Reportedly, cytokine activin C is mainly expressed in small-diameter dorsal root ganglion (DRG) neurons and suppresses inflammatory pain. However, the effects of activin C in neuropathic pain remain elusive.

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Intranasal oxytocin as a treatment for chronic pelvic pain: A randomized controlled feasibility study.

To investigate the effect of intranasal oxytocin on chronic pelvic pain in a randomized, double-blind, within-subject crossover trial. Aims included: (1) determine intranasal oxytocin's effect on pain intensity and pain interference relative to placebo; (2) assess feasibility and acceptability.

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Intrinsic braking role of descending locus coeruleus noradrenergic neurons in acute and chronic itch in mice.

Itch is defined as an unpleasant sensation that provokes a desire to scratch. Our understanding of neuronal circuits for itch information transmission and processing in the spinal dorsal horn (SDH) has progressively advanced following the identification of SDH neuron subsets that are crucial for scratching behavior in models of itch. However, little is known about the control of acute and chronic itch by descending signals from the brain to the SDH. In this study, using genetic approaches that enable cell-type and circuit-specific functional manipulation, we reveal an intrinsic potential of locus coeruleus (LC)-noradrenergic (NAergic) neurons that project to the SDH to control acute and chronic itch. Activation and silencing of SDH-projecting LC-NAergic neurons reduced and enhanced scratching behavior, respectively, in models of histamine-dependent and -independent acute itch. Furthermore, in a model of chronic itch associated with contact dermatitis, repetitive scratching behavior was suppressed by the activation of the descending LC-NAergic pathway and by knocking out NA transporters specific to descending LC-NAergic neurons using a CRISPR-Cas9 system. Moreover, patch-clamp recording using spinal slices showed that noradrenaline facilitated inhibitory synaptic inputs onto gastrin-releasing peptide receptor-expressing SDH neurons, a neuronal subset known to be essential for itch transmission. Our findings suggest that descending LC-NAergic signaling intrinsically controls acute and chronic itch and provide potential therapeutic strategies for the treatment of acute and chronic itch.

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Differences in personality, perceived stress and physical activity in women with burning mouth syndrome compared to controls.

Objectives Burning mouth syndrome (BMS) is a long-lasting pain condition which is commonly associated with anxiety symptoms and experience of adverse, stressful life events have been reported by those diagnosed with the syndrome. Stress-related biomarkers have been related to personality traits in BMS and a personality with high stress susceptibility and perceived stress may be of importance. Although biopsychosocial approaches are suggested to manage long-lasting orofacial pain, to date little is known about physical activity in women with BMS. The aim of this study was to investigate if personality, perceived stress and physical activity distinguish women with BMS from controls. Methods Fifty-six women with BMS and 56 controls matched on age and gender completed Swedish universities Scales of Personality (SSP), Perceived Stress Questionnaire (PSQ) and a general questionnaire with an item on weekly physical activity frequency. In addition, health-related quality of life was explored by additional questionnaires and reported in a companion article (Jedel et al. Scand J Pain. 2020. PubMed PMID: 32853174). Results SSP subscales Somatic Trait Anxiety, Psychic Trait Anxiety, Stress Susceptibility and Verbal Trait Aggression differed between women with BMS and controls and the personality factor scores for Neuroticism and Aggressiveness were higher. Perceived stress measured by PSQ index was higher for women with BMS compared to controls. Women with BMS reported lower physical activity frequency compared to controls and those reporting physical activity <4 days/week scored higher on PSQ compared to those with weekly physical activity ≥4 days/week. Conclusions Personality distinguished women with BMS from controls in this study. Perceived stress was higher and weekly physical activity was lower in women with BMS compared to controls. Our findings suggest physical activity should be more comprehensively measured in future BMS studies and, by extension, physical activity may be a treatment option for women with BMS. Pain management aiming to restore function and mobility with stress reduction should be considered in clinical decision making for women with BMS who have a personality with stress susceptibility, especially if reporting high perceived stress and insufficient physical activity.

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Symptoms of central sensitization in patients with inflammatory bowel diseases: a case-control study examining the role of musculoskeletal pain and psychological factors.

Objectives Musculoskeletal (MSK) pain is a common complaint in patients with inflammatory bowel diseases (IBD). MSK pain in IBD has previously demonstrated association with symptoms of central sensitization; however it is uncertain whether these symptoms are influenced simply by the presence of MSK pain and/or IBD. Primary aim of this study was to investigate whether symptoms of central sensitization differed across three groups: IBD patients with and without MSK pain and healthy controls. Secondary aim was to investigate between-group differences for measures of somatosensory functioning. Methods Cross-sectional study was performed on adults with IBD. Assessments included: central sensitization inventory (CSI), pressure pain threshold, temporal summation, conditioned pain modulation, perceived stress, affect style, anxiety, depression, and pain catastrophizing. One-way analyses of variance and covariance were used to investigate between-group differences for measures of central sensitization and potential confounding by psychological factors. Results Study participants (n=66) were age/gender matched across three study groups. Between-group differences were solely demonstrated for CSI scores [F(2,63)=19.835, p<0.001, r=0.62], with IBD patients with MSK pain demonstrating the highest CSI scores and healthy controls the lowest. After controlling for individual psychological features, post hoc comparisons indicated that CSI scores were significantly different between-groups (p≤0.025) after controlling for most psychological variables, with the exception of perceived stress (p=0.063) and pain catastrophizing (p=0.593). Conclusions IBD patients as a whole demonstrated significantly greater symptoms of central sensitization compared to healthy controls. However, IBD patients with persistent MSK pain demonstrated the greatest symptoms of central sensitization compared to patients without MSK pain and healthy controls. Between-group differences for CSI in IBD patients with MSK were not confounded by psychological features. Implications Study results indicate that persistent MSK pain in IBD represents patients with greater central sensitization symptomology. This increased symptomology is suggestive of underlying mechanisms related to central sensitization, highlighting patient potentially at risk for worse pain experiences.

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The association between selected genetic variants and individual differences in experimental pain.

Objectives The underlying mechanisms for individual differences in experimental pain are not fully understood, but genetic susceptibility is hypothesized to explain some of these differences. In the present study we focus on three genetic variants important for modulating experimental pain related to serotonin (SLC6A4 5-HTTLPR/rs25531 A>G), catecholamine (COMT rs4680 Val158Met) and opioid (OPRM1 rs1799971 A118G) signaling. We aimed to investigate associations between each of the selected genetic variants and individual differences in experimental pain. Methods In total 356 subjects (232 low back pain patients and 124 healthy volunteers) were genotyped and assessed with tests of heat pain threshold, pressure pain thresholds, heat pain tolerance, conditioned pain modulation (CPM), offset analgesia, temporal summation and secondary hyperalgesia. Low back pain patients and healthy volunteers did not differ in regards to experimental test results or allelic frequencies, and were therefore analyzed as one group. The associations were tested using analysis of variance and the Kruskal-Wallis test. Results No significant associations were observed between the genetic variants (SLC6A4 5-HTTLPR/rs25531 A>G, COMT rs4680 Val158Met and OPRM1 rs1799971 A118G) and individual differences in experimental pain (heat pain threshold, pressure pain threshold, heat pain tolerance, CPM, offset analgesia, temporal summation and secondary hyperalgesia). Conclusions The selected pain-associated genetic variants were not associated with individual differences in experimental pain. Genetic variants well known for playing central roles in pain perception failed to explain individual differences in experimental pain in 356 subjects. The finding is an important contribution to the literature, which often consists of studies with lower sample size and one or few experimental pain assessments.

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Amelioration of Compound 48/80-Mediated Itch and LL-37-Induced Inflammation by a Single-Stranded Oligonucleotide.

Numerous inflammatory skin disorders display a high prevalence of itch. The Mas-related G protein coupled receptor X2 (MRGPRX2) has been shown to modulate itch by inducing non-IgE-mediated mast cell degranulation and the release of endogenous inducers of pruritus. Various substances collectively known as basic secretagogues, which include inflammatory peptides and certain drugs, can trigger MRGPRX2 and thereby induce pseudo-allergic reactions characterized by histamine and protease release as well as inflammation. Here, we investigated the capacity of an immunomodulatory single-stranded oligonucleotide (ssON) to modulate IgE-independent mast cell degranulation and, more specifically, its ability to inhibit the basic secretagogues compound 48/80 (C48/80)-and LL-37 and . We examined the effect of ssON on MRGPRX2 activation by measuring degranulation in a human mast cell line (LAD2) and calcium influx in MRGPRX2-transfected HEK293 cells. To determine the effect of ssON on itch, we performed behavioral studies in established mouse models and collected skin biopsies for histological analysis. Additionally, with the use of a rosacea mouse model and RT-qPCR, we investigated the effect on ssON on LL-37-induced inflammation. We reveal that both mast cell degranulation and calcium influx in MRGPRX2 transfected HEK293 cells, induced by the antimicrobial peptide LL-37 and the basic secretagogue C48/80, are effectively inhibited by ssON in a dose-dependent manner. Further, ssON demonstrates a capability to inhibit LL-37 and C48/80 activation in two mouse models. We show that intradermal injection of ssON in mice is able to block itch induced via C48/80 in a dose-dependent manner. Histological staining revealed that ssON inhibits acute mast cell degranulation in murine skin treated with C48/80. Lastly, we show that ssON treatment ameliorates LL-37-induced inflammation in a rosacea mouse model. Since there is a need for new therapeutics targeting non-IgE-mediated activation of mast cells, ssON could be used as a prospective drug candidate to resolve itch and inflammation in certain dermatoses.

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Prevalence of analgesic use in patients with chronic pain referred to a multidisciplinary pain centre and its correlation with patient-reported outcome measures: A cross-sectional, registry-based study.

Chronic pain is prevalent in Sweden, nearing 20% in the adult population. Treatment often requires a multimodal approach, with medication, physical therapy and psychological interventions. However, the frequency of medication in patients with chronic pain in Sweden, and its correlation with patient-reported outcome measures (PROMs), are currently unknown.

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Investigating the Effects of Cuing Medication Availability on Patient-controlled Analgesia Pump Usage in Pediatric Patients: Results of a Randomized Controlled Trial.

The study of Patient-Controlled Analgesia (PCA) behaviors has led to greater understanding of factors that affect the pain experience. Although PCA behaviors can be influenced by cues to medication availability, no studies have examined the effects of such cues in pediatric populations.

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Role of the CXCR4/ALK5/Smad3 Signaling Pathway in Cancer-Induced Bone Pain.

The chemokine receptor, CXCR4, and the transforming growth factor-beta receptor, ALK5, both contribute to various processes associated with the sensation of pain. However, the relationship between CXCR4 and ALK5 and the possible mechanisms promoted by ALK5 in the development of pain have not been evaluated.

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Aging-Related Phenotypic Conversion of Medullary Microglia Enhances Intraoral Incisional Pain Sensitivity.

Activated microglia involved in the development of orofacial pain hypersensitivity have two major polarization states. The aim of this study was to assess the involvement of the aging-related phenotypic conversion of medullary microglia in the enhancement of intraoral pain sensitivity using senescence-accelerated mice (SAM)-prone/8 (SAMP8) and SAM-resistant/1 (SAMR1) mice. Mechanical head-withdrawal threshold (MHWT) was measured for 21 days post palatal mucosal incision. The number of CD11c-immunoreactive (IR) cells [affective microglia (M1)] and CD163-IR cells [protective microglia (M2)], and tumor-necrosis-factor-α (TNF-α)-IR M1 and interleukin (IL)-10-IR M2 were analyzed via immunohistochemistry on days 3 and 11 following incision. The decrease in MHWT observed following incision was enhanced in SAMP8 mice. M1 levels and the number of TNF-α-IR M1 were increased on day 3 in SAMP8 mice compared with those in SAMR1 mice. On day 11, M1 and M2 activation was observed in both groups, whereas IL-10-IR M2 levels were attenuated in SAMP8 mice, and the number of TNF-α-IR M1 cells increased, compared to those in SAMR1 mice. These results suggest that the mechanical allodynia observed following intraoral injury is potentiated and sustained in SAMP8 mice due to enhancement of TNF-α signaling, M1 activation, and an attenuation of M2 activation accompanying IL-10 release.

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A contemporary neuroscience approach compared to biomedically focused education combined with symptom-contingent exercise therapy in people with chronic whiplash associated disorders: a randomized controlled trial protocol.

To address the need for a better treatment of chronic whiplash associated disorders (WAD), a contemporary neuroscience approach can be proposed.

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Fear of movement and (re)injury is associated with condition specific outcomes and health-related quality of life in women with patellofemoral pain.

Investigate the association of fear of movement and (re)injury with clinical outcomes in women with patellofemoral pain (PFP).

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Flare Size but Not Intensity Reflects Histamine-Induced Itch.

Flare reactions arise due to the release of vasodilators from sensory nerves caused by antidromic transmission of action potentials after the induction of itch.

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Digital manikins to self-report pain on a smartphone: a systematic review of mobile apps.

Chronic pain is the leading cause of disability. Improving our understanding of pain occurrence and treatment effectiveness requires robust methods to measure pain at scale. Smartphone-based pain manikins are human-shaped figures to self-report location-specific aspects of pain on people's personal mobile devices.

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Approximation to pain-signaling network in humans by means of migraine.

Nociceptive signals are processed within a pain-related network of the brain. Migraine is a rather specific model to gain insight into this system. Brain networks may be described by white matter tracts interconnecting functionally defined gray matter regions. Here, we present an overview of the migraine-related pain network revealed by this strategy. Based on diffusion tensor imaging data from subjects in the Human Connectome Project (HCP) database, we used a global tractography approach to reconstruct white matter tracts connecting brain regions that are known to be involved in migraine-related pain signaling. This network includes an ascending nociceptive pathway, a descending modulatory pathway, a cortical processing system, and a connection between pain-processing and modulatory areas. The insular cortex emerged as the central interface of this network. Direct connections to visual and auditory cortical association fields suggest a potential neural basis of phono- or photophobia and aura phenomena. The intra-axonal volume (V ) as a measure of fiber integrity based on diffusion microstructure was extracted using an innovative supervised machine learning approach in form of a Bayesian estimator. Self-reported pain levels of HCP subjects were positively correlated with tract integrity in subcortical tracts. No correlation with pain was found for the cortical processing systems.

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Prescription and Prescriber Specialty Characteristics of Initial Opioid Prescriptions Associated with Chronic Use.

This study evaluated the characteristics of opioid prescriptions, including prescriber specialty, given to opioid-naïve patients and their association with chronic use.

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Noninvasive vagal nerve stimulation for gastroenterology pain disorders.

Abdominal pain continues to be a major challenge and unmet need in clinical practice. Normalization of bidirectional gut-brain signaling has generated much interest as a therapeutic approach to treat chronic abdominal pain. Vagal nerve stimulation (VNS) is emerging as a potential non-pharmacologic strategy for the treatment of abdominal pain. In this review paper, we will summarize the etiologies of chronic pain in gastrointestinal disorders and discuss the rational for VNS as a therapeutic approach to chronic abdominal pain, with particular emphasis in the gammaCore stimulator which allows for noninvasive VNS.

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α6GABA Receptor Positive Modulators Alleviate Migraine-like Grimaces in Mice via Compensating GABAergic Deficits in Trigeminal Ganglia.

Migraine is caused by hyperactivity of the trigeminovascular system, where trigeminal ganglia (TG) play an important role. This hyperactivity might originate from an underfunctional GABAergic system in TG. To investigate this possibility, we adapted a mouse model of migraine by inducing migraine-like grimaces in male mice via repeated injections of nitroglycerin (NTG, 10 mg/kg, i.p.), once every 2 days, for up to 5 sessions. Migraine-like facial pain scores were measured using the mouse grimace scale. Repeated NTG treatments in mice caused significant increases in migraine-like grimaces that were aborted and prevented by two anti-migraine agents sumatriptan and topiramate, respectively. After 5 sessions of NTG injections, the GABA-synthesizing enzyme, 65-kDa glutamate decarboxylase (GAD65), but not the GABA transporter 1 (GAT1) or the α6 subunit-containing GABA receptors (α6GABARs), was downregulated in mouse TG tissues. Taking advantage of the unaffected TG α6GABAR expression in NTG-treated mice, we demonstrated that an α6GABAR-selective positive allosteric modulator (PAM), DK-I-56-1, exhibited both abortive and prophylactic effects, comparable to those of sumatriptan and topiramate, respectively, in this migraine-mimicking mouse model. The brain-impermeable furosemide significantly prevented the effects of DK-I-56-1, suggesting its peripheral site of action, likely via preventing α6GABAR modulation in TG. Results suggest that a decreased GABA synthesis caused by the reduced GAD65 expression in TG contributes to the trigeminovascular activation in this repeated NTG-induced migraine-mimicking model and that the unaltered α6GABARs in TG are potential targets for migraine treatment. Thus, α6GABAR-selective PAMs are potential anti-migraine agents for both abortive and preventive therapies.

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The effect of temporal information on placebo analgesia and nocebo hyperalgesia.

Expectations are known to be key determinants of placebo and nocebo phenomena. In previous studies, verbal suggestions to induce such expectations have mainly focused on the direction and magnitude of the effect while little is known about the influence of temporal information.

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Intravascular Endothelin-1 does not trigger or increase susceptibility to Spreading Depolarizations.

Spreading depolarizations (SD) likely manifest as aura in migraineurs. Triggers are unknown although vascular events have been implicated. Direct carotid puncture has been reported to trigger migraine with aura. The potent vasoconstrictor endothelin-1 (ET-1), which can be released from the endothelium under pathological conditions, may play a role. Here, we tested whether intracarotid ET-1 infusion triggers SD and whether systemic ET-1 infusion increases the susceptibility to SD.

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The impact of prurigo nodularis on quality of life: a systematic review and meta-analysis.

Prurigo nodularis (PN) is a chronic, pruritic, debilitating disease. Previous studies found that chronic pruritus in general negatively affects patients' quality of life (QoL). However, results about the impact of PN on QoL are conflicting. Our objective was to assess the QoL burden of PN. A systematic review was conducted of all published studies that assessed QoL measures in PN. OVID MEDLINE, EMBASE, SCOPUS, and Web of Science were searched. Pooled meta-analysis (means) was performed using random-effects weighting. Overall, 13 studies met inclusion criteria. All studies identified QoL reductions in patients suffering from PN compared to control groups. The most common QoL instrument used was the Dermatology Life Quality Index [n = 9 studies; pooled mean (95% confidence interval): 13.8 (10.6-16.9), denoting a very large effect]. In particular, PN was associated with substantial impact on multiple domains of QoL. No publication bias was detected. In conclusion, QoL is negatively impacted in PN. Future studies are necessary to determine the best instruments of measuring QoL in PN patients, better understand this association, and assess the impact in males and females separately. PROSPERO CRD42019136193.

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Effectiveness of onabotulinumtoxinA (BOTOX) in pediatric patients experiencing migraines: a randomized, double-blinded, placebo-controlled crossover study in the pediatric pain population.

OnabotulinumtoxinA (OBTA) is approved for treating chronic headaches and migraines in adults, but there is limited scientific literature on the outcomes in pediatric patients. The aim of this study was to determine if subjects treated with OBTA reported a statistically significant improvement in the primary features (frequency, intensity, duration and disability scoring) associated with migraines compared with placebo at follow-up visits.

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Digital Pain Mapping and Tracking in Patients With Chronic Pain: Longitudinal Study.

Digital pain mapping allows for remote and ecological momentary assessment in patients over multiple time points spanning days to months. Frequent ecological assessments may reveal tendencies and fluctuations more clearly and provide insights into the trajectory of a patient's pain.

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The safety of medications used to treat peripheral neuropathic pain, part 2 (opioids, cannabinoids and other drugs): review of double-blind, placebo-controlled, randomized clinical trials.

Peripheral neuropathic pain is a highly disabling condition for patients and a challenge for physicians. Although many drugs have been assessed in scientific studies, few have demonstrated clear clinical efficacy against neuropathic pain. Moreover, the paucity of data regarding their safety raises the question of the benefit-risk ratio when used in patients experiencing peripheral neuropathies.

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The role of perioperative ketamine in postoperative pain control following spinal surgery.

Opioid abuse has rapidly developed into an epidemic across the United States. Patients are often introduced to opioids following surgical procedures-this is particularly relevant following spinal surgery. Surgeons can help reduce this opioid burden by finding alternatives to narcotic analgesia in the postoperative period. One such medication that has shown potential in this role is ketamine, which has been studied in various surgical specialties. A review was performed of current literature regarding ketamine use in the perioperative period specific to spinal surgery. This review focused on prospective randomized control trials; the primary endpoint was opioid consumption in the postoperative period, monitored through patient-controlled analgesia (PCA) use. Both pediatric and adult spinal surgery patients were included; cervical, thoracic, and lumbar procedures were also all included. 10 studies were selected for this reviewed based on inclusion criteria, published between 2004 and 2017. 7 of these studies demonstrated a significant decrease in postoperative opioid use with the integration of ketamine in the perioperative period, while 3 trials showed no significant difference in opioid consumption. There is inherent difficulty in standardizing studies of this nature-dosing protocols, medication timing, and supplemental analgesia were variable throughout the included studies. However, this review of the most up-to-date prospective studies indicate ketamine has potential to play a significant role in reducing opioid requirements following spinal surgery, and further study is warranted in this field.

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An Unorthodox Mechanism Underlying Voltage Sensitivity of TRPV1 Ion Channel.

While the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) channel is a polymodal nociceptor for heat, capsaicin, and protons, the channel's responses to each of these stimuli are profoundly regulated by membrane potential, damping or even prohibiting its response at negative voltages and amplifying its response at positive voltages. Therefore, voltage sensitivity of TRPV1 is anticipated to play an important role in shaping pain responses. How voltage regulates TRPV1 activation remains unknown. Here, it is shown that voltage sensitivity does not originate from the S4 segment like classic voltage-gated ion channels; instead, outer pore acidic residues directly partake in voltage-sensitive activation, with their negative charges collectively constituting the observed gating charges. Outer pore gating-charge movement is titratable by extracellular pH and is allosterically coupled to channel activation, likely by influencing the upper gate in the ion selectivity filter. Elucidating this unorthodox voltage-gating process provides a mechanistic foundation for understanding TRPV1 polymodal gating and opens the door to novel approaches regulating channel activity for pain management.

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Direct Peripheral Nerve Stimulation for the Treatment of Complex Regional Pain Syndrome: A 30-Year Review.

Complex regional pain syndrome (CRPS), formerly known as reflex sympathetic dystrophy (RSD), is a difficult to treat condition characterized by debilitating pain and limitations in functional ability. Neuromodulation, in the form of spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS), have been traditionally used as a treatment for CRPS with variable success.

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Spinal neuronal excitability and neuroinflammation in a model of chemotherapeutic neuropathic pain: targeting the resolution pathways.

Neuroinflammation is a critical feature of sensitisation of spinal nociceptive processing in chronic pain states. We hypothesised that the resolvin pathways, a unique endogenous control system, may ameliorate aberrant spinal processing of somatosensory inputs associated with chemotherapy-induced neuropathic pain (CINP).

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Leptin Contributes to Neuropathic Pain via Extrasynaptic NMDAR-nNOS Activation.

Leptin is an adipocytokine that is primarily secreted by white adipose tissue, and it contributes to the pathogenesis of neuropathic pain in collaboration with N-methyl-D-aspartate receptors (NMDARs). Functional NMDARs are a heteromeric complex that primarily comprise two NR1 subunits and two NR2 subunits. NR2A is preferentially located at synaptic sites, and NR2B is enriched at extrasynaptic sites. The roles of synaptic and extrasynaptic NMDARs in the contribution of leptin to neuropathic pain are not clear. The present study examined whether the important role of leptin in neuropathic pain was related to synaptic or extrasynaptic NMDARs. We used a rat model of spared nerve injury (SNI) and demonstrated that the intrathecal administration of the NR2A-selective antagonist NVP-AAM077 and the NR2B-selective antagonist Ro25-6981 prevented and reversed mechanical allodynia following SNI. Administration of exogenous leptin mimicked SNI-induced behavioral allodynia, which was also prevented by NVP-AAM077 and Ro25-6981. Mechanistic studies showed that leptin enhanced NR2B- but not NR2A-mediated currents in spinal lamina II neurons of naïve rats. Leptin also upregulated the expression of NR2B, which was blocked by the NR2B-selective antagonist Ro25-6981, in cultured dorsal root ganglion (DRG) neurons. Leptin enhanced neuronal nitric oxide synthase (nNOS) expression, which was also blocked by Ro25-6981, in cultured DRG cells. However, leptin did not change NR2A expression, and the NR2A-selective antagonist NVP-AAM077 had no effect on leptin-enhanced nNOS expression. Our data suggest an important cellular link between the spinal effects of leptin and the extrasynaptic NMDAR-nNOS-mediated cellular mechanism of neuropathic pain.

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Introduction of a psychologically informed educational intervention for pre-licensure physical therapists in a classroom setting.

There is an increasing need for physical therapists to address psychosocial aspects of musculoskeletal pain. Psychologically informed practice is one way to deliver this type of care through the integration of biopsychosocial interventions into patient management. An important component of psychologically informed practice is patient centered communication. However, there is little research on how to effectively implement patient centered communication into pre-licensure training for physical therapists.

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Primary culture of the rat spinal dorsal horn: a tool to investigate the effects of inflammatory stimulation on the afferent somatosensory system.

One maladaptive consequence of inflammatory stimulation of the afferent somatosensory system is the manifestation of inflammatory pain. We established and characterized a neuroglial primary culture of the rat superficial dorsal horn (SDH) of the spinal cord to test responses of this structure to neurochemical, somatosensory, or inflammatory stimulation. Primary cultures of the rat SDH consist of neurons (43%), oligodendrocytes (35%), astrocytes (13%), and microglial cells (9%). Neurons of the SDH responded to cooling (7%), heating (18%), glutamate (80%), substance P (43%), prostaglandin E (8%), and KCl (100%) with transient increases in the intracellular calcium [Ca]. Short-term stimulation of SDH primary cultures with LPS (10 μg/ml, 2 h) caused increased expression of pro-inflammatory cytokines, inflammatory transcription factors, and inducible enzymes responsible for inflammatory prostaglandin E synthesis. At the protein level, increased concentrations of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) were measured in the supernatants of LPS-stimulated SDH cultures and enhanced TNFα and IL-6 immunoreactivity was observed specifically in microglial cells. LPS-exposed microglial cells further showed increased nuclear immunoreactivity for the inflammatory transcription factors NFκB, NF-IL6, and pCREB, indicative of their activation. The short-term exposure to LPS further caused a reduction in the strength of substance P as opposed to glutamate-evoked Ca-signals in SDH neurons. However, long-term stimulation with a low dose of LPS (0.01 μg/ml, 24 h) resulted in a significant enhancement of glutamate-induced Ca transients in SDH neurons, while substance P-evoked Ca signals were not influenced. Our data suggest a critical role for microglial cells in the initiation of inflammatory processes within the SDH of the spinal cord, which are accompanied by a modulation of neuronal responses.

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Effect of First-Line Ziconotide Intrathecal Drug Therapy for Neuropathic Pain on Disability, Emotional Well-Being and Pain Catastrophizing.

Previous studies demonstrate decreased pain scores with ziconotide as a first-line agent for intrathecal drug therapy(IDT). Subset analysis suggests that patients with neuropathic pain have greater improvement. Here we prospectively examine the role of first-line ziconotide IDT on the tridimensional pain experience in ziconotide IDT naïve patients with neuropathic pain.

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Predictors of engagement in an internet-based cognitive behavioral therapy program for veterans with chronic low back pain.

Internet-based interventions for chronic pain have demonstrated efficacy and may address access barriers to care. Participant characteristics have been shown to affect engagement with these programs; however, limited information is available about the relationship between participant characteristics and engagement with internet-based programs for self-management of chronic pain. The current study examined relationships between demographic and clinical characteristics and engagement with the Pain EASE program, a self-directed, internet-based cognitive behavioral therapy intervention for veterans with chronic low back pain (cLBP). Veterans with cLBP were enrolled in a 10 week trial of the Pain EASE program. Engagement measures included the number of logins, access to coping skill modules, and completed study staff-initiated weekly check-in calls. Regression analyses were conducted to identify significant predictors of engagement from hypothesized predictors (e.g., race/ethnicity, age, depressive symptom severity, and pain interference). Participants (N = 58) were 93% male, 60.3% identified as White, and had a mean age of 54.5 years. Participants logged into the program a median of 3.5 times, accessed a median of 2 skill modules, and attended a median of 6 check-in calls. Quantile regression revealed that, at the 50th percentile, non-White-identified participants accessed fewer modules than White-identified participants (p = .019). Increased age was associated with increased module use (p = .001). No clinical characteristics were significantly associated with engagement measures. White-identified race/ethnicity and increased age were associated with greater engagement with the Pain EASE program. Results highlight the importance of defining and increasing engagement in internet-delivered pain care.

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Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor antagonists.

Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown clinically to be effective treatments for migraine. Zavegepant (BHV-3500, BMS-742413) is a high affinity antagonist of the CGRP receptor (hCGRP K = 0.023 nM) that has demonstrated efficacy in the acute treatment of migraine with intranasal delivery in a Phase 2/3 trial, despite showing low oral bioavailability in rats (F = 1.7%). Using zavegepant as a template, we sought to improve oral bioavailability through a series of azepinones which were designed in an attempt to reduce the number of rotatable bonds. These efforts led to the discovery of compound 21 which was able to mostly maintain high affinity binding (hCGRP K = 0.100 nM) and in vivo efficacy in the marmoset facial blood flow assay, while greatly improving oral bioavailability (rat F = 17%).

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Anti-hypernociceptive and anti-inflammatory effects of JM-20: A novel hybrid neuroprotective compound.

The present study examines the possible effect of the novel hybrid molecule JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-411-dihydro-1H-pyrido[2,3-b] [1,5] benzodiazepine) on pain-related behaviours in a persistent pain model (5% formalin test) and in the neutrophil migration events during the inflammatory process. It further introduces JM-20 in a chronic constriction injury (CCI) model to clarify the possible subjacent mechanisms with its consequent clinical relevance. A single administration of JM-20 (20 or 40 mg/kg, per os [p.o.]) decreased licking/biting exclusively in the tonic phase of the formalin test in a GABA/benzodiazepine (BZD) receptor antagonist flumazenil-sensitive manner. JM-20 reduced in vivo neutrophil migration, rolling and adhesion to the endothelium induced by intraperitoneal administration of carrageenan in mice. In addition, plasma extravasation and tumour necrosis factor alpha production in the peritoneal fluid were decreased. Treatment with JM-20 (20 mg/kg, p.o.) for 7 days after CCI reduced mechanical hypersensitivity in a NG-monomethyl-l-arginine (L-NMMA)/methylene blue/glibenclamide-sensitive manner. Histopathological signs of Wallerian degeneration (WD) of the sciatic nerve were also attenuated, as well as interleukin-1 beta release in the spinal cord. The nitrate/nitrite concentration was increased centrally and did not show differences at the peripheral nerve level. The findings of this study suggest JM-20 can decrease persistent pain. A transient activity of its BDZ portion on nociceptive pathways mediated by GABA/BZD receptors in association with its anti-inflammatory properties could be at least partially involved in this effect. JM-20 decreased CCI-induced mechanical hypersensitivity via the l-arginine/nitric oxide (NO)/cyclic GMP-sensitive ATP-sensitive potassium channel pathway. Its neuroprotective ability by preventing WD could be implicated in its anti-neuropathic mechanisms.

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Resting-State Magnetoencephalography Reveals Neurobiological Bridges Between Pain and Cognitive Impairment.

Pain has been identified as a risk factor for cognitive dysfunction, which in turn affects pain perception. Although pain, cognitive dysfunction, and their interaction are clinically important, the neural mechanism connecting the two phenomena remains unclear.

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Digital Self-Management in Support of Patients Living With Chronic Pain: Feasibility Pilot Study.

Chronic pain can be complex and taxing to live with, and treatment and support require a multicomponent approach, which may not always be offered or available. Smartphones, tablets, and personal computers are already incorporated into patients' daily lives, and therefore, they can be used to communicate, educate, and support self-management. Although some web-based self-management interventions exist, research examining the evidence and effect of digital solutions supporting self-management for patients living with chronic pain is limited, findings are inconclusive, and new innovative ideas and solutions are needed.

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Validity and Reliability of the Computer-Administered Routine Opioid Outcome Monitoring (ROOM) Tool.

The Routine Opioid Outcome Monitoring (ROOM) tool measures outcomes with opioids using an established framework which includes domains such as pain, mood, opioid use disorder, alcohol use, and constipation. This study aims to validate and establish the test-retest reliability of the computer-administered ROOM tool.

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