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Papers: 28 Nov 2020 - 4 Dec 2020

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The sociocultural context of pediatric pain: an examination of the portrayal of pain in children’s popular media.

Pain (eg, needle injections, injuries, and chronic pain) is highly prevalent in childhood and occurs in social contexts. Nevertheless, broader sociocultural influences on pediatric pain, such as popular media, have not been empirically examined. This study examined how pain is portrayed and gendered in children's popular media. A cross-section of children's media targeted towards 4- to 6-year-old children was selected based on popularity, including 10 movies and the first season of 6 television shows. Pain instances were extracted and coded using 2 established observational coding systems assessing sufferer pain characteristics and observer responses (eg, empathic responses). Findings identified 454 instances of pain across the selected media. Violent pain (ie, intentionally inflicted) and injuries were most commonly represented, whereas everyday, chronic-type, and procedural pains were infrequently portrayed. Pain instances were more commonly experienced by boy characters, who also expressed greater distress; yet, observers were more responsive (eg, expressed greater concern) towards girl characters' pain. Overall, observer responses to pain were infrequent, with observers witnessing but not responding to nearly half of pain instances. Observers who did respond expressed an overall lack of empathy towards sufferers. These findings reveal a very narrow depiction of pain presented in children's popular media, with an overall underrepresentation of pain, numerous maladaptive portrayals of pain, and gender differences in both sufferer and observer responses. This study underscores the need for further research to inform how children's popular media is perceived by parents and children and how media may be transformed and harnessed for effective pain education in childhood.

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Discoveries in structure and physiology of mechanically activated ion channels.

The ability to sense physical forces is conserved across all organisms. Cells convert mechanical stimuli into electrical or chemical signals via mechanically activated ion channels. In recent years, the identification of new families of mechanosensitive ion channels-such as PIEZO and OSCA/TMEM63 channels-along with surprising insights into well-studied mechanosensitive channels have driven further developments in the mechanotransduction field. Several well-characterized mechanosensory roles such as touch, blood-pressure sensing and hearing are now linked with primary mechanotransducers. Unanticipated roles of mechanical force sensing continue to be uncovered. Furthermore, high-resolution structures representative of nearly every family of mechanically activated channel described so far have underscored their diversity while advancing our understanding of the biophysical mechanisms of pressure sensing. Here we summarize recent discoveries in the physiology and structures of known mechanically activated ion channel families and discuss their implications for understanding the mechanisms of mechanical force sensing.

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Oral steroids for episodic cluster headache.

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Enhancing analgesic spinal cord stimulation for chronic pain with personalized immersive virtual reality.

Spinal cord stimulation (SCS) is an approved treatment for truncal and limb neuropathic pain. However, pain relief is often suboptimal and SCS efficacy may reduce over time, sometimes requiring addition of other pain therapies, stimulator revision, or even explantation. We designed and tested a new procedure by combining SCS with immersive virtual reality (VR) to enable analgesia in patients with chronic leg pain. We coupled SCS and VR by linking SCS-induced paresthesia with personalized visual bodily feedback that was provided by VR and matched to the spatio-temporal patterns of SCS-induced paresthesia. In this cross-sectional prospective interventional study, fifteen patients with severe chronic pain and an SCS implant underwent congruent SCS-VR (personalized visual feedback of the perceived SCS-induced paresthesia displayed on the patient's virtual body) and two control conditions (incongruent SCS-VR; VR alone). We demonstrate the efficacy of neuromodulation-enhanced VR for the treatment of chronic pain by showing that congruent SCS-VR reduced pain ratings on average by 44%. SCS-VR analgesia was stronger than in both control conditions (enabling stronger analgesic effects than incongruent SCS-VR analgesia or VR alone), and kept increasing over successive stimulations, revealing the selectivity and consistency of the observed effects. We also show that analgesia persists after congruent SCS-VR had stopped, indicating carry over effects and underlining its therapeutic potential. Linking latest VR technology with recent insights from the neuroscience of body perception and SCS-neuromodulation, our personalized new SCS-VR platform highlights the impact of immersive digiceutical therapies for chronic pain.

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Open-label placebo for chronic low back pain: a 5-year follow-up.

Long-term follow-up of patients treated with open-label placebo (OLP) are non-existent. Herein, we report a 5-year follow-up of a three-weeks OLP randomized controlled trial (RCT) in chronic low back pain patients. We re-contacted the original participants of original RCT and reassessed their pain, disability, and use of pain medication. We obtained follow-up data from 55 participants (82% of those who took OLP during the parent RCT), with a mean elapsed time between the end of the 3-weeks placebo trial and the follow-up interview of 55 months (SD=7.85). We found significant reductions in both pain and disability between the baseline assessment immediately before the three-weeks trial with placebo pills and the original trial endpoint (p < .00001 for the two primary outcomes of pain and disability). At the 5-year follow-up, we found no significant differences in either outcome between original trial endpoint and follow-up. Improvements persisted after 5-years and were accompanied by substantial reductions compared to baseline in the use of pain medication (from 87% to 38%), comprising analgesics (from 80% to 31%) antidepressants (from 24% to 11%), and benzodiazepines (from 15% to 5%). In contrast, the use of alternative approaches to pain management increased (from 18% to 29%). Although the reduction in pain and medication is comparable to the improvements that occurred in the original study, a major limitation of this long-term follow-up is the absence of controls for spontaneous improvement and new co-interventions. Nonetheless, our data suggest that reductions in pain and disability following OLP may be long lasting.

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Phenotypic profile clustering pragmatically identifies diagnostically and mechanistically informative subgroups of chronic pain patients.

Traditional classification and prognostic approaches for chronic pain conditions focus primarily on anatomically based clinical characteristics not based on underlying biopsychosocial factors contributing to perception of clinical pain and future pain trajectories. Using a supervised clustering approach in a cohort of temporomandibular disorder (TMD) cases and controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, we recently developed and validated a rapid algorithm (ROPA) to pragmatically classify chronic pain patients into three groups that differed in clinical pain report, biopsychosocial profiles, functional limitations, and comorbid conditions. The present aim was to examine the generalizability of this clustering procedure in two additional cohorts: a cohort of patients with chronic overlapping pain conditions (Complex Persistent Pain Conditions (CPPC) study), and a real-world clinical population of patients seeking treatment at Duke Innovative Pain Therapies (DIPT). In each cohort, we applied ROPA for cluster prediction, which requires only four input variables: pressure pain threshold (PPT) and anxiety, depression, and somatization scales. In both CPPC and DIPT, we distinguished three clusters, including one with more severe clinical characteristics and psychological distress. We observed strong concordance with observed cluster solutions, indicating the ROPA method allows for reliable subtyping of clinical populations with minimal patient burden. The ROPA clustering algorithm represents a rapid and valid stratification tool independent of anatomic diagnosis. ROPA holds promise in classifying patients based on pathophysiological mechanisms rather than structural or anatomical diagnoses. As such, this method of classifying patients will facilitate personalized pain medicine for patients with chronic pain.

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Intranasal delivery of an antisense oligonucleotide to the RNA-binding protein HuR relieves nerve injury-induced neuropathic pain.

Neuropathic pain remains an undertreated condition and there is a medical need to develop effective treatments. Accumulating evidence indicates that post-transcriptional regulation of gene expression is involved in neuropathic pain; however, RNA processing is not clearly investigated. Our study investigated the role of HuR, an RNA binding protein, in promoting neuropathic pain and trauma-induced microglia activation in the spared nerve injury (SNI) mouse model. To this aim, an antisense oligonucleotide (ASO) knockdown of HuR gene expression was used. ASOs poorly cross the blood brain barrier and an intranasal (i.n.) administration was employed to achieve CNS penetration through a noninvasive delivery. The efficacy of i.n. ASO administration was compared to an intrathecal (i.t.) delivery. I.n. administered ASO reduced spinal HuR protein and relieved pain hypersensitivity with a similar efficacy to i.t. administration. Immunofluorescence studies showed that HuR was expressed in activated microglia, co-localized with p38 and, partially, with extracellular signal-regulated kinase (ERK)1/2 within the spinal cord dorsal horn. An anti-HuR ASO inhibited the activation of spinal microglia by reducing the levels of pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS), the activation of nuclear factor-κB (NF-κB), and suppressed the SNI-induced overphosphorylation of spinal p38, ERK1/2 and c-Jun-N-terminal kinase (JNK)-1. In addition, HuR silencing increased the expression of the anti-inflammatory cytokine IL-10, promoting the shift of microglial M1 to M2 phenotype. Targeting HuR by i.n. anti-HuR ASO might represent a noninvasive promising perspective for neuropathic pain management by its powerful inhibition of microglia-mediated spinal neuroinflammation and promotion of an anti-inflammatory and neuroprotectant response.

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Fabry disease pain: patient and preclinical parallels.

Severe neuropathic pain is a hallmark of Fabry disease, a genetic disorder caused by a deficiency in lysosomal α-Galactosidase A. Pain experienced by these patients significantly impacts their quality of life and ability to perform everyday tasks. Fabry patients suffer from peripheral neuropathy, sensory abnormalities, acute pain crises, and lifelong ongoing pain. Although treatment of pain through medication and enzyme replacement therapy (ERT) exists, pain persists in many of these patients. Some has been learned in the past decades regarding clinical manifestations of pain in Fabry disease and the pathological effects of α-Galactosidase A insufficiency in neurons. Still, it is unclear how pain and sensory abnormalities arise in Fabry patients and how these can be targeted with therapeutics. Our knowledge is limited in part due to the lack of adequate preclinical models to study the disease. This review will detail the types of pain, sensory abnormalities, influence of demographics on pain, and current strategies to treat pain experienced by Fabry patients. In addition, we discuss the current knowledge of Fabry pain pathogenesis and which aspects of the disease preclinical models accurately recapitulate. Understanding the commonalities and divergences between humans and preclinical models can be utilized to further interrogate mechanisms causing the pain and sensory abnormalities as well as advance development of the next generation of therapeutics to treat pain in Fabry patients.

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C5a complement and cytokine signaling mediate the pronociceptive effects of complex regional pain syndrome patient IgM in fracture mice.

It has been proposed that Complex Regional Pain Syndrome (CRPS) is a post-traumatic autoimmune disease. Previously we observed that B cells contribute to CRPS-like changes in a mouse tibia fracture model, and that early (< 12 months duration) CRPS patient IgM antibodies have pronociceptive effects in the skin and spinal cord of muMT fracture mice lacking B cells. The current study evaluated the pronociceptive effects of intraplantar or intrathecal injections of early CRPS IgM (5ug) in muMT fracture mice. Skin and lumbar spinal cord were collected for immunohistochemistry and polymerase chain reaction (PCR) analyses. Wildtype mice exhibited post fracture increases in complement component C5a and its receptor expression in skin and spinal cord, predominantly on dermal macrophages and spinal microglia. Intraplantar IgM injection caused nociceptive sensitization in muMT fracture mice with increased complement component C1q and inflammatory cytokine expression, and these IgM effects were blocked by a C5a receptor antagonist (PMX53) or a global cytokine inhibitor (pentoxifylline). Intrathecal IgM injection also had pronociceptive effects with increased spinal cytokine expression, effects that were blocked by PMX53 or pentoxifylline treatment. Intrathecal injection of chronic (> 12 months duration) CRPS patient IgM (but not IgG) caused nociceptive sensitization in muMT fracture mice, but intraplantar injection of chronic CRPS IgM or IgG had no effect. We postulate that CRPS IgM antibodies bind to neoantigens in the fracture limb skin and corresponding spinal cord to activate C5a complement signaling in macrophages and microglia, evoking proinflammatory cytokine expression contributing to nociceptive sensitization in the injured limb.

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Increase in trigeminal ganglion neurons that respond to both CGRP and PACAP in mouse models of chronic migraine and post-traumatic headache.

A large body of animal and human studies indicate that blocking peripheral calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) signaling pathways may prevent migraine episodes and reduce headache frequency. To investigate whether recurring migraine episodes alter the strength of CGRP and PACAP signaling in trigeminal ganglion (TG) neurons, we compared the number of TG neurons that respond to CGRP and to PACAP (CGRP-R and PACAP-R, respectively) under normal and chronic migraine-like conditions. In a mouse model of chronic migraine, repeated nitroglycerin (NTG) administration significantly increased the number of CGRP-R and PACAP-R neurons in TG but not dorsal root ganglia. In TG neurons that express endogenous αCGRP, repeated NTG led to a 7-fold increase in the number of neurons that respond to both CGRP and PACAP (CGRP-R&PACAP-R). The majority of these neurons were unmyelinated C-fiber nociceptors. This suggests that a larger fraction of CGRP signaling in TG nociceptors may be mediated through the autocrine mechanism, and the release of endogenous αCGRP can be enhanced by both CGRP and PACAP signaling pathways under chronic migraine condition. The number of CGRP-R&PACAP-R TG neurons was also increased in a mouse model of post-traumatic headache (PTH). Interestingly, low-dose interleukin-2 treatment, which completely reverses chronic migraine- and PTH-related behaviors in mouse models, also blocked the increase in both CGRP-R and PACAP-R TG neurons. Together, these results suggest that inhibition of both CGRP and PACAP signaling in TG neurons may be more effective in treating chronic migraine and PTH than targeting individual signaling pathways.

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Predicting pain: differential pain thresholds during self-induced, externally induced, and imagined self-induced pressure pain.

During self-induced pain, a copy of the motor information from the body's own movement may help predict the painful sensation and cause down-regulation of pain. This phenomenon, called sensory attenuation, enables the distinction between self-produced stimuli versus stimuli produced by others. Sensory attenuation has been shown to occur also during imagined self-produced movements, but this has not been investigated for painful sensations. In the current study, the pressure pain thresholds of 40 healthy participants aged 18-35 years were assessed when pain was induced by the experimenter (other), by themselves (self), or by the experimenter while imagining the pressure to be self-induced (imagery). The pressure pain was induced on the participants left lower thigh (quadriceps femoris) using a hand-held algometer. Significant differences were found between all conditions: other and self (P < 0.001), other and imagery (P < 0.001), and self and imagery (P = 0.004). The mean pressure pain threshold for other was 521.49 kPa (SE = 38.48), for self 729.57 kPa (SE = 32.32), and for imagery 618.88 kPa (SE = 26.67). Thus, sensory attenuation did occur both in the self and the imagery condition. The results of this study may have clinical relevance for understanding the mechanisms involved in the elevated pain thresholds seen in patients with self-injury behavior and the low pain thresholds seen in patients with chronic pain conditions. Imagery of sensory attenuation might also be used to alleviate the pain experience for patients undergoing procedural pain.

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Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: a multicentre, double-blind, randomised controlled trial.

Prednisone is commonly used for initial short-term therapy of episodic cluster headaches before preventive medication such as verapamil becomes effective, but this strategy has not been tested in large randomised trials. We aimed to access the safety and efficacy of this treatment approach.

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The conformational cycle of a prototypical voltage-gated sodium channel.

Electrical signaling was a dramatic development in evolution, allowing complex single-cell organisms like Paramecium to coordinate movement and early metazoans like worms and jellyfish to send regulatory signals rapidly over increasing distances. But how are electrical signals generated in biology? In fact, voltage-gated sodium channels conduct sodium currents that initiate electrical signals in all kingdoms of life, from bacteria to man. They are responsible for generating the action potential in vertebrate nerve and muscle, neuroendocrine cells, and other cell types. Because of the high level of conservation of their core structure, it is likely that their fundamental mechanisms of action are conserved as well. Here we describe the complete cycle of conformational changes that a bacterial sodium channel undergoes as it transitions from resting to activated/open and inactivated/closed states, based on high-resolution structural studies of a single sodium channel. We further relate this conformational cycle of the ancestral sodium channel to the function of its vertebrate orthologs. The strong conservation of amino acid sequence and three-dimensional structure suggests that this model, at a fundamental level, is relevant for both prokaryotic and eukaryotic sodium channels, as well as voltage-gated calcium and potassium channels.

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Recent advances in neurotechnologies with broad potential for neuroscience research.

Interest in deciphering the fundamental mechanisms and processes of the human mind represents a central driving force in modern neuroscience research. Activities in support of this goal rely on advanced methodologies and engineering systems that are capable of interrogating and stimulating neural pathways, from single cells in small networks to interconnections that span the entire brain. Recent research establishes the foundations for a broad range of creative neurotechnologies that enable unique modes of operation in this context. This review focuses on those systems with proven utility in animal model studies and with levels of technical maturity that suggest a potential for broad deployment to the neuroscience community in the relatively near future. We include a brief summary of existing and emerging neuroscience techniques, as background for a primary focus on device technologies that address associated opportunities in electrical, optical and microfluidic neural interfaces, some with multimodal capabilities. Examples of the use of these technologies in recent neuroscience studies illustrate their practical value. The vibrancy of the engineering science associated with these platforms, the interdisciplinary nature of this field of research and its relevance to grand challenges in the treatment of neurological disorders motivate continued growth of this area of study.

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Prevalence and risk factors of migraine and non-migraine headache in older people – results of the Heinz Nixdorf Recall study.

The prevalence of migraine and non-migraine headache declines with age.

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Reversion from chronic migraine to episodic migraine following treatment with erenumab: Results of a analysis of a randomized, 12-week, double-blind study and a 52-week, open-label extension.

To determine reversion rates from chronic migraine to episodic migraine during long-term erenumab treatment.

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Protein synthesis primes neurons for migraine pain.

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NF-κB-mediated effects on behavior and cartilage pathology in a non-invasive loading model of post-traumatic osteoarthritis.

This study aimed to examine the temporal activation of NF-κB and its relationship to the development of pain-related sensitivity and behavioral changes in a non-invasive murine knee loading model of PTOA.

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Headache complexity (number of symptom features) differentiates post-traumatic from non-traumatic headaches.

Post-traumatic headaches are a common sequela of mild traumatic brain injury (concussion). It is unclear whether or how these headaches differ phenotypically from primary headaches.

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A Conceptual Model of Biopsychosocial Mechanisms of Transition from Acute to Chronic Postsurgical Pain in Children and Adolescents.

Acute and chronic pain are highly prevalent and impactful consequences of surgery across the lifespan, yet a comprehensive conceptual model encompassing biopsychosocial factors underlying acute to chronic pain transition is lacking, particularly in youth. Building on prior chronic postsurgical pain models, we propose a new conceptual model of biopsychosocial mechanisms of transition from acute to chronic postsurgical pain. This review aims to summarize existing research examining key factors underlying acute to chronic postsurgical pain transition in order to guide prevention and intervention efforts aimed at addressing this health issue in children. As pain transitions from acute nociceptive pain to chronic pain, changes in the peripheral and central nervous system contribute to the chronification of pain after surgery. These changes include alterations in sensory pain processing and psychosocial processes (psychological, behavioral, and social components), which promote the development of chronic pain. Patient-related premorbid factors (eg, demographic factors, genetic profile, and medical factors such as premorbid pain) may further modulate these changes. Factors related to acute injury and recovery (eg, surgical and treatment factors), as well as biological response to surgery (eg, epigenetic, inflammatory, and endocrine factors), may also influence this process. Overall, longitudinal studies examining temporal pathways of biopsychosocial processes including both risk and resiliency factors will be essential to identify the mechanisms involved in the transition from acute to chronic pain. Research is also needed to unravel connections between the acute pain experience, opioid exposure, and sensory pain processing during acute to chronic pain transition. Furthermore, future studies should include larger and more diverse samples to more fully explore risk factors in a broader range of pediatric surgeries. The use of conceptual models to guide intervention approaches targeting mechanisms of transition from acute to chronic pain will significantly advance this field and improve outcomes for children and adolescents undergoing surgery.

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The influence of rat strain on the development of neuropathic pain and comorbid anxio-depressive behaviour after nerve injury.

Back-translating the clinical manifestations of human disease burden into animal models is increasingly recognized as an important facet of preclinical drug discovery. We hypothesized that inbred rat strains possessing stress hyper-reactive-, depressive- or anxiety-like phenotypes may possess more translational value than common outbred strains for modeling neuropathic pain. Rats (inbred: LEW, WKY, F344/ICO and F344/DU, outbred: Crl:SD) were exposed to Spared Nerve Injury (SNI) and evaluated routinely for 6 months on behaviours related to pain (von Frey stimulation and CatWalk-gait analysis), anxiety (elevated plus maze, EPM) and depression (sucrose preference test, SPT). Markers of stress reactivity together with spinal/brain opioid receptor expression were also measured. All strains variously developed mechanical allodynia after SNI with the exception of stress-hyporesponsive LEW rats, despite all strains displaying similar functional gait-deficits after injury. However, affective changes reflective of anxiety- and depressive-like behaviour were only observed for F344/DU in the EPM, and for Crl:SD in SPT. Although differences in stress reactivity and opioid receptor expression occurred, overall they were relatively unaffected by SNI. Thus, anxio-depressive behaviours did not develop in all strains after nerve injury, and correlated only modestly with degree of pain sensitivity or with genetic predisposition to stress and/or affective disturbances.

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A linguistic analysis of future narratives in adolescents with Complex Regional Pain Syndrome and their pain-free peers.

Complex Regional Pain Syndrome (CRPS) is a chronic pain condition that often develops after injury, with a typical onset in adolescence. The impact of chronic pain is far-reaching, with many adolescents reporting atypical developmental trajectories compared with peers. Social Comparison Theory offers a framework for understanding how such comparisons influence wellbeing, whereby a heightened sense of disparity places adolescents at risk of poor cognitive, affective and social outcomes. Using a novel linguistic analysis programme, this study aims to investigate cognitive, affective and social language used by adolescents with CRPS in comparison to their peers during a task reflecting on their futures.

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Child pain-related injustice appraisals mediate the relationship between just-world beliefs and pain-related functioning.

Research among adult and pediatric samples suggests that pain-related injustice appraisals contribute to adverse pain-related functioning. However, a singular focus on pain-related injustice appraisals carries the risk of underestimating the role of broader concepts of justice. This study examined the unique roles of child pain-related injustice appraisals and just-world beliefs in understanding disability and physical, emotional, social, and academic functioning, as well as the mediating role of injustice appraisals in the relationship between just-world beliefs and functioning.

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Transcranial direct current stimulation of the dorsolateral prefrontal cortex alters emotional modulation of spinal nociception.

Emotion has a strong modulatory effect on pain perception and spinal nociception. Pleasure inhibits pain and nociception, whereas displeasure facilitates pain and nociception. Dysregulation of this system has been implicated in development and maintenance of chronic pain. The current study sought to examine whether emotional modulation of pain could be altered through the use of transcranial direct current stimulation (tDCS) to enhance (via anodal stimulation) or depress (via cathodal stimulation) cortical excitability in the dorsolateral prefrontal cortex. Thirty-two participants (15 female, 17 male) received anodal, cathodal, and sham tDCS on three separate occasions, followed immediately by testing to examine the impact of pleasant and unpleasant images on pain and nociceptive flexion reflex (NFR) responses to electrocutaneous stimulation. Results indicated that tDCS modulated the effect of image content on NFR, F(2, 2175.06) = 3.20, p = 0.04, with the expected linear slope following anodal stimulation (i.e., pleasant < neutral < unpleasant) but not cathodal stimulation. These findings provide novel evidence that the dorsolateral prefrontal cortex is critical to emotional modulation of spinal nociception. Moreover, the results suggest a physiological basis for a previously identified phenotype associated with risk for chronic pain and thus a potentially new target for chronic pain prevention efforts. PERSPECTIVE: This study demonstrated that reduction of dorsolateral prefrontal cortical excitability by transcranial direct current stimulation attenuates the impact of emotional image viewing on nociceptive reflex activity during painful electrocutaneous stimulation. This result confirms there is cortical involvement in emotional modulation of spinal nociception and opens avenues for future clinical research.

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Advanced age attenuates the antihyperalgesic effect of morphine and decreases μ-opioid receptor expression and binding in the rat midbrain periaqueductal gray in male and female rats.

The present study investigated the impact of advanced age on morphine modulation of persistent inflammatory pain in male and female rats. The impact of age, sex, and pain on μ-opioid receptor (MOR) expression and binding in the ventrolateral periaqueductal gray (vlPAG) was also examined using immunohistochemistry and receptor autoradiography. Intraplantar administration of complete Freund's adjuvant induced comparable levels of edema and hyperalgesia in adult (2-3 mos) and aged (16-18 mos) male and female rats. Morphine potency was highest in adult males, with a greater than two-fold increase in morphine EC observed in adult versus aged males (3.83 mg/kg vs. 10.16 mg/kg). Adult and aged female rats also exhibited significantly higher EC values (7.76 mg/kg and 8.74 mg/kg, respectively) than adult males. The upward shift in EC from adult to aged males was paralleled by a reduction in vlPAG MOR expression and binding. The observed age-related reductions in morphine potency and vlPAG MOR expression and binding have significant implications in pain management in the aged population.

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Reversion mutation of cDNA CA8-204 minigene construct produces a truncated functional peptide that regulates calcium release in vitro and produces profound analgesia in vivo.

Intracellular calcium is critical in orchestrating neuronal excitability and analgesia. Carbonic anhydrase-8 (CA8) regulates intracellular calcium signaling through allosteric inhibition of neuronal inositol trisphosphate receptor 1 (ITPR1) to produce profound analgesia. Recently, we reported the "G" allele at rs6471859 represents cis-eQTL regulating alternative splicing of a 1697 bp transcript (CA8-204) with a retained intron, alternative polyadenylation site and a new stop codon producing a functional 26 kDa peptide with an extended exon 3. In this study we show the reversion mutation (G to C) at rs6471859 within the CA8-204 expression vector also produced a stable 1697 bp transcript (CA8-204) coding for a smaller peptide (~ 22 kDa) containing only the first three CA8 exons. Surprisingly, this peptide inhibited ITPR1 (pITPR1) activation, ITPR1-mediated calcium release in vitro; and produced profound analgesia in vivo. This is the first report showing CA8-204 codes for a functional peptide sufficient to regulate calcium signaling and produce profound analgesia.

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Novel inhibitory brainstem neurons with selective projections to spinal lamina I reduces both pain and itch.

Sensory information is transmitted from peripheral nerves, through the spinal cord, and up to the brain ("bottom up" pathway). Some of this information may be modulated by "top-down" projections from the brain to the spinal cord. Discovering endogenous mechanisms for reducing pain and itch holds enormous potential for developing new treatments. However, neurons mediating the top-down inhibition of pain are not well understood, nor has any such pathway been identified for itch sensation. Here we identify a novel population of GABAergic neurons in the ventral brainstem, distinguished by prodynorphin expression, which we named LJA5. LJA5 neurons provide the only known inhibitory projection specifically to lamina I of the spinal cord, which contains sensory neurons that transmit pain and itch information up to the brain. Chemogenetically activating LJA5 neurons in male mice reduces capsaicin-induced pain and histamine-induced itch. Identifying this new pathway opens new treatment opportunities for chronic, refractory pain and pruritis. This article is protected by copyright. All rights reserved.

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Interictal amylin levels in chronic migraine patients: A case-control study.

Recently, amylin and its receptors were found in different structures involved in migraine pathophysiology. Here, we evaluate interictal concentrations of amylin and calcitonin gene-related peptide in peripheral blood as biomarkers for chronic migraine.

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Migraine remains second among the world’s causes of disability, and first among young women: findings from GBD2019.

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Predicting the Future of Migraine Attack Prediction.

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Inducing positive emotions to reduce chronic pain: a randomized controlled trial of positive psychology exercises.

Positive emotions have been found to be analgesic and can be induced by positive psychology exercises. This study tested if positive psychology exercises provide beneficial effects on pain, responses to pain, physical (pain interference), and emotional function.

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Animal Models for Functional Gastrointestinal Disorders.

Functional gastrointestinal disorders (FGID), such as functional dyspepsia (FD) and irritable bowel syndrome (IBS) are characterized by chronic abdominal symptoms in the absence of an organic, metabolic or systemic cause that readily explains these complaints. Their pathophysiology is still not fully elucidated and animal models have been of great value to improve the understanding of the complex biological mechanisms. Over the last decades, many animal models have been developed to further unravel FGID pathophysiology and test drug efficacy. In the first part of this review, we focus on stress-related models, starting with the different perinatal stress models, including the stress of the dam, followed by a discussion on neonatal stress such as the maternal separation model. We also describe the most commonly used stress models in adult animals which brought valuable insights on the brain-gut axis in stress-related disorders. In the second part, we focus more on models studying peripheral, i.e., gastrointestinal, mechanisms, either induced by an infection or another inflammatory trigger. In this section, we also introduce more recent models developed around food-related metabolic disorders or food hypersensitivity and allergy. Finally, we introduce models mimicking FGID as a secondary effect of medical interventions and spontaneous models sharing characteristics of GI and anxiety-related disorders. The latter are powerful models for brain-gut axis dysfunction and bring new insights about FGID and their comorbidities such as anxiety and depression.

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Preoperative risk factors associated with chronic pain profiles following total knee arthroplasty.

One in five patients experiences chronic pain 12 months following total knee arthroplasty (TKA). This longitudinal study used a person-centered approach to identify subgroups of patients with distinct chronic pain profiles following TKA and identified preoperative characteristics associated with these profiles.

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Development and Validation of a Daily Injustice Experience Questionnaire.

Patterns of cognitive appraisal related to chronic pain may manifest differentially across time due to a variety of factors, but variability of injustice appraisals across time has not been examined. The current study details the validation of a brief, daily version of the Injustice Experience Questionnaire (IEQ), which measures injustice appraisals related to the experience of pain and disability.

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Early life chronic inflammatory conditions predict low back pain in adolescence and young adulthood.

Associations between inflammatory conditions and low back pain (LBP) have been found frequently in older populations. However, the nature of these relationships in younger populations is unknown. This study aimed to investigate associations between early life chronic or recurrent inflammatory conditions and impactful LBP in adolescence and young adulthood.

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A Critical Review of the Social and Behavioral Contributions to the Overdose Epidemic.

More than 750,000 people in the United States died from an overdose between 1999 and 2018; two-thirds of those deaths involved an opioid. In this review, we present trends in opioid overdose rates during this period and discuss how the proliferation of opioid prescribing to treat chronic pain, changes in the heroin and illegally manufactured opioid synthetics markets, and social factors, including deindustrialization and concentrated poverty, contributed to the rise of the overdose epidemic. We also examine how current policies implemented to address the overdose epidemic may have contributed to reducing prescription opioid overdoses but increased overdoses involving illegal opioids. Finally, we identify new directions for research to understand the causes and solutions to this critical public health problem, including research on heterogeneous policy effects across social groups, effective approaches to reduce overdoses of illegal opioids, and the role of social contexts in shaping policy implementation and impact. Expected final online publication date for the , Volume 42 is April 1, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Sensitization of Cutaneous Primary Afferents in Bone Cancer Revealed by In Vivo Calcium Imaging.

Cancer-induced bone pain (CIBP) is a complex condition, comprising components of inflammatory and neuropathic processes, but changes in the physiological response profiles of bone-innervating and cutaneous afferents remain poorly understood. We used a combination of retrograde labelling and in vivo calcium imaging of bone marrow-innervating dorsal root ganglia (DRG) neurons to determine the contribution of these cells in the maintenance of CIBP. We found a majority of femoral bone afferent cell bodies in L3 dorsal root ganglia (DRG) that also express the sodium channel subtype Na1.8-a marker of nociceptive neurons-and lack expression of parvalbumin-a marker for proprioceptive primary afferents. Surprisingly, the response properties of bone marrow afferents to both increased intraosseous pressure and acid were unchanged by the presence of cancer. On the other hand, we found increased excitability and polymodality of cutaneous afferents innervating the ipsilateral paw in cancer bearing animals, as well as a behavioural phenotype that suggests changes at the level of the DRG contribute to secondary hypersensitivity. This study demonstrates that cutaneous afferents at distant sites from the tumour bearing tissue contribute to mechanical hypersensitivity, highlighting these cells as targets for analgesia.

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Why is exercise prescribed for people with chronic low back pain? A review of the mechanisms of benefit proposed by clinical trialists.

Exercise is recommended for the management of chronic low back pain (CLBP). Trialists have proposed numerous mechanisms to explain why exercise improves pain and function in people with CLBP, but these are yet to be synthesised.

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Pain burden, sensory profile and inflammatory cytokines of dogs with naturally-occurring neuropathic pain treated with gabapentin alone or with meloxicam.

Canine neuropathic pain (NeuP) has been poorly investigated. This study aimed to evaluate the pain burden, sensory profile and inflammatory cytokines in dogs with naturally-occurring NeuP. Twenty-nine client-owned dogs with NeuP were included in a prospective, partially masked, randomized crossover clinical trial, and treated with gabapentin/placebo/gabapentin-meloxicam or gabapentin-meloxicam/placebo/gabapentin (each treatment block of 7 days; total 21 days). Pain scores, mechanical (MNT) and electrical (ENT) nociceptive thresholds and descending noxious inhibitory controls (DNIC) were assessed at baseline, days 7, 14, and 21. DNIC was evaluated using ΔMNT (after-before conditioning stimulus). Positive or negative ΔMNT corresponded to inhibitory or facilitatory pain profiles, respectively. Pain scores were recorded using the Client Specific Outcome Measures (CSOM), Canine Brief Pain Inventory (CBPI), and short-form Glasgow Composite Measure Pain Scale (CMPS-SF). Data from baseline were compared to those of sixteen healthy controls. ΔMNT, but not MNT and ENT, was significantly larger in controls (2.3 ± 0.9 N) than in NeuP (-0.2 ± 0.7 N). The percentage of dogs with facilitatory sensory profile was similar at baseline and after placebo (61.5-63%), and between controls and after gabapentin (33.3-34.6%). The CBPI scores were significantly different between gabapentin (CBPI pain and CBPI overall impression) and/or gabapentin-meloxicam (CBPI pain and interference) when compared with baseline, but not placebo. The CBPI scores were not significantly different between placebo and baseline. The concentration of cytokines was not different between groups or treatments. Dogs with NeuP have deficient inhibitory pain mechanisms. Pain burden was reduced after gabapentin and/or gabapentin-meloxicam when compared with baseline using CBPI and CMPS-SF scores. However, these scores were not superior than placebo, nor placebo was superior to baseline evaluations. A caregiver placebo effect may have biased the results.

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Diagnostic uncertainty in pediatric chronic pain: nature, prevalence, and consequences.

Diagnostic uncertainty (DU), which is the perception that a label or explanation for a patient's health problem is missing or inaccurate, has been linked to distress, anxiety, and difficulty coping among adults with pain. This study examined the prevalence of DU among youth with chronic pain and their parents and the relation of parent and youth DU with youth pain, pain-related constructs, and health-related quality of life (HRQoL).

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Systematic scoping review of interactions between analgesic drug therapy and mindfulness-based interventions for chronic pain in adults: current evidence and future directions.

Most patients with chronic pain do not find adequate pain relief with a single treatment, and accumulating evidence points to the added benefits of rational combinations of different treatments. Given that psychological therapies, such as mindfulness-based interventions (MBIs), are often delivered in conjunction with concomitant analgesic drug therapies (CADTs), this systematic scoping review examines the evidence for any interactions between MBIs and CADTs. The protocol for this review has been published and registered. MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and PsycINFO databases were searched until July 2019. We included randomized controlled trials that evaluated the efficacy of MBIs for the treatment of chronic pain. A total of 40 randomized controlled trials (2978 participants) were included. Thirty-nine of 40 (97.5%) included mindfulness-based clinical trials allowed the use of CADTs. However, only 6 of these 39 (15.4%) trials provided adequate details of what these CADTs were, and only 4 (10.3%) trials controlled for CADTs. Of great relevance to this review, none of the included trials analyzed the interactions between MBIs and the CADTs to determine whether they have an additive, synergistic, or antagonistic effect on chronic pain. Adverse events were inconsistently reported, and no judgment could be made about safety. Future trials assessing the interactions between MBIs and CADTs, with better harms reporting, are needed to better define the role of MBIs in the management of chronic pain.

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Eptinezumab for the Prevention of Episodic Migraine: Sustained Effect Through 1 Year of Treatment in the PROMISE-1 Study.

The Prevention of Migraine via Intravenous ALD403 Safety and Efficacy 1 (PROMISE-1) study was a phase III, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy, tolerability, and pharmacokinetic properties of repeat intravenous (IV) doses of the calcitonin gene-related peptide‒targeted monoclonal antibody eptinezumab (ALD403) for migraine prevention in adults with episodic migraine. Here we present the results of PROMISE-1 through 1 year of treatment (up to 4 doses).

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Migraine Headache Day Response Rates and the Implications to Patient Functioning: An Evaluation of 3 Randomized Phase 3 Clinical Trials of Galcanezumab in Patients With Migraine.

This post hoc study investigated the relationship between patient response in terms of migraine headache day reduction and patient-reported outcomes of health-related quality of life (HRQoL) and disability categories.

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The Cyclical Relation Between Chronic Pain, Executive Functioning, Emotional Regulation, and Self-Management.

To propose a new model outlining a hypothesized cyclical relation between executive functioning, emotional regulation, and chronic pain in adolescence and to highlight the likely importance of such a relation for self-management behavior and pain-related disability.

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Additive Analgesic Effect of Transcranial Direct Current Stimulation Together with Mirror Therapy for the Treatment of Phantom Pain.

Current analgesic treatments for phantom pain are not optimal. One well-accepted yet limited nonpharmacological option is mirror therapy, which is thought to counterbalance abnormal plasticity. Transcranial direct current stimulation (tDCS) is an emerging approach believed to affect the membrane potential and activity threshold of cortical neurons. tDCS analgesic effectiveness, however, is mild and short, rendering it a noneffective stand-alone treatment. This study aimed to assess if a combination of mirror therapy with tDCS results in a superior analgesic effect as compared with mirror therapy alone in patients suffering from phantom pain due to recent amputation.

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Nociceptive, emotional, electrophysiological, and histological characterization of the chronic constriction injury model in female Wistar Han rats.

Chronic neuropathic pain affects 7-10% of the population and is often accompanied by comorbid emotional disorders, which greatly reduce the quality of life of the patients, impairing physical, cognitive, emotional, and social functioning. Despite the higher prevalence and severity of chronic pain in women, the number of publications using female animals remains scarce. While in the chronic constriction injury (CCI) model the development of mechanical/thermal hyperalgesia, allodynia and spontaneous pain has been shown in both sexes, little is known on CCI-induced emotional impairments and sciatic nerve histopathology in female rats, as well as on the contributions of ovarian hormones to peripheral nerve injury. In this work, young adult rats (Wistar Han) were assigned to one of five groups: gonadally intact females (SHAM/SHAM), ovariectomized females (SHAM/OVX), gonadally intact females with CCI (CCI/SHAM); ovariectomized females with CCI (CCI/OVX) and males with CCI (CCI). In the postoperative period, CCI animals, both females and males, displayed visible gait abnormalities, limping and guarding the affected hind paw although locomotion was not affected. Neuropathic females developed sustained mechanical allodynia, with CCI/OVX animals displaying symptoms two weeks before CCI/SHAM females. Interestingly, regarding mechanical and cold allodynia, CCI males slowly recovered from week 3 onwards. While CCI induced neither anxiety- nor depressive-like behaviour in females, ovariectomy per se induced anhedonic-like behaviour, regardless of CCI surgery. Histopathological analysis of the sciatic nerve showed CCI induced nerve damage, fibrosis, myelin sheath degradation and inflammation. Single-cell electrophysiological data from the rostral ventromedial medulla (RVM) suggests this area is partly involved in descending facilitation associated with experimental neuropathic pain. Altogether, our findings demonstrate CCI females display distinct sensory, emotional, electrophysiological, and histopathological impairments from males, and that ovariectomy aggravates females' responses to peripheral nerve injury.

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Differential modulation of the anterior cingulate and insular cortices on anxiogenic-like responses induced by empathy for pain.

Mice cohabiting with a conspecific in chronic pain display anxiogenesis in the elevated plus-maze (EPM). Given that the anterior cingulate (ACC) and insular (InC) cortices play a role in the modulation of anxiety, pain, and emotional contagion, we investigated (a) the FosB activation in both brain areas and (b) the effects of intra-ACC or -InC injection of cobalt chloride (CoCl, a synaptic blocker), on the anxiety of mice cohabiting with a cagemate suffering pain. Twenty-one days after birth, male Swiss mice were housed in pairs for 14 days to establish familiarity. On the 14th day, mice were divided into two groups: cagemate sciatic nerve constriction (CNC; i.e., one animal of each pair was subjected to sciatic nerve constriction), and cagemate sham (CS; i.e., a similar procedure but without suffering nerve constriction). After that, both groups were housed again with the same pairs for the other 14 days. On the 28th day, mice had their brains removed for the immunoassays analyses (Exp. 1). For experiments 2 and 3, on the 23rd day, the cagemates received guide cannula implantation bilaterally in the ACC or InC and, on the 28th day, they received local injections of saline or CoCl, and then were exposed to the EPM. Results showed that cohabitation with a conspecific with chronic pain decreases and increases neuronal activation (FosB) within the ACC and InC, respectively. Intra-ACC or InC injection of CoCl reversed the anxiogenic effect in those animals that cohabited with a conspecific in chronic pain. ACC and InC seem to modulate anxiety induced by emotional contagion in animals cohabitating with a conspecific suffering pain.

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Neuropathic pain in children: Steps towards improved recognition and management.

Neuropathic pain in children can be severe and persistent, difficult to recognise and manage, and associated with significant pain-related disability. Recognition based on clinical history and sensory descriptors is challenging in young children, and screening tools require further validation at older ages. Confirmatory tests can identify the disease or lesion of the somatosensory nervous system resulting in neuropathic pain, but feasibility and interpretation may be influenced by age- and sex-dependent changes throughout development. Quantitative sensory testing identifies specific mechanism-related sensory profiles; brain imaging is a potential biomarker of alterations in central processing and modulation of both sensory and affective components of pain; and genetic analysis can reveal known and new causes of neuropathic pain. Alongside existing patient- and parent-reported outcome measures, somatosensory system research methodologies and validation of mechanism-based standardised end-points may inform individualised therapy and stratification for clinical trials that will improve evidence-based management of neuropathic pain in children.

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The PAR2 inhibitor I-287 selectively targets Gα and Gα signaling and has anti-inflammatory effects.

Protease-activated receptor-2 (PAR2) is involved in inflammatory responses and pain, therefore representing a promising therapeutic target for the treatment of immune-mediated inflammatory diseases. However, as for other GPCRs, PAR2 can activate multiple signaling pathways and those involved in inflammatory responses remain poorly defined. Here, we describe a new selective and potent PAR2 inhibitor (I-287) that shows functional selectivity by acting as a negative allosteric regulator on Gα and Gα activity and their downstream effectors, while having no effect on G signaling and βarrestin2 engagement. Such selective inhibition of only a subset of the pathways engaged by PAR2 was found to be sufficient to block inflammation in vivo. In addition to unraveling the PAR2 signaling pathways involved in the pro-inflammatory response, our study opens the path toward the development of new functionally selective drugs with reduced liabilities that could arise from blocking all the signaling activities controlled by the receptor.

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Headaches in Adults in Primary Care: Evaluation, Diagnosis, and Treatment.

Headaches are common in primary care. The diagnosis is made by a careful history and physical examination. Imaging is generally not warranted. Several general principles underlie the acute treatment of headache: early initiation of therapy and adequate dosing at first dose. Careful attention to avoiding too frequent administration of acute therapy is important to avoid medication overuse headaches. Opioids should always be avoided. Preventive treatment is indicated for frequent headaches. Successful treatment entails low-dose medication with careful titration and monitoring of headache frequency. Behavioral strategies are important and should be part of any comprehensive headache management plan.

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A non-randomized pilot study to test the feasibility of treating chronic pain and opioid prescription use in rural areas with acceptance and commitment therapy (T-PACT).

Chronic non-cancer pain (CNCP) involves one-third of the US population, and prescription opioids contribute to the opioid epidemic. The Centers for Disease Control and Prevention emphasizes maximizing non-opioid treatment, but many rural populations cannot access alternative therapies. Clinical and Translational Science Award hubs across four rural states performed a multi-site, single-arm intervention feasibility study testing methods and procedures of implementing a behavioral intervention, acceptance and commitment therapy, in primary care CNCP patients on chronic opioids. Using the CONSORT extension for feasibility studies, we describe lessons learned in recruiting/retaining participants, intervention implementation, data measurement, and multi-site procedures. Results inform a future definitive trial and potentially others conducting rural trials.

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DNA Microarray Analysis of Differential Gene Expression in the Dorsal Root Ganglia of Four Different Neuropathic Pain Mouse Models.

Pathological stimuli or injury to the peripheral nervous system can trigger neuropathic pain with common clinical features such as allodynia and hypersensitivity. Although various studies have identified molecules or genes related to neuropathic pain, the essential components are still unclear. Therefore, in this study, we investigated the molecular and genetic factors related to neuropathic pain.

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Anodal transcranial direct current stimulation in chronic migraine and medication overuse headache: A pilot double-blind randomized sham-controlled trial.

Little evidence is available on the role of transcranial direct current stimulation (tDCS) in patients affected by chronic migraine (CM) and medication overuse headache (MOH). We aim to investigate the effects of tDCS in patients with CM and MOH as well as its role on brain activity.

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Latest Insights into the Pathophysiology of Migraine: the ATP-Sensitive Potassium Channels.

Migraine remains a challenging condition to treat, thus highlighting the need for a better understanding of its molecular mechanisms. This review intends to unravel a new emerging target in migraine pathophysiology, the adenosine 5'-triphosphate-sensitive K (K) channel.

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Polypharmacy and comorbidities during pregnancy in a cohort of women with migraine.

To describe longitudinal patterns of medication use throughout pregnancy in women with migraine.

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Characterization of Preoperative, Postsurgical, Acute and Chronic Pain in High Risk Breast Cancer Patients.

Pain after breast cancer surgery remains largely unexplained and inconsistently quantified. This study aims to describe the perioperative pain patterns in patients with breast cancer, up to two years after surgery.

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The Potential Contribution of Chronic Pain and Common Chronic Pain Conditions to Subsequent Cognitive Decline, New Onset Cognitive Impairment, and Incident Dementia: A Systematic Review and Conceptual Model for Future Research.

Growing evidence suggests that chronic pain and certain chronic pain conditions may increase risk for cognitive decline and dementia.

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Risk and Resilience Factors Impacting Treatment Compliance and Functional Impairment among Adolescents Participating in an Outpatient Interdisciplinary Pediatric Chronic Pain Management Program.

Recurrent pain is a common experience in childhood and adolescence and can result in significant disability in youth, including poor quality of life, school absences, and reduced social activities. Evidence has linked adolescent risk and resilience factors with treatment outcomes. However, less research has focused on examining risk and resilience factors that may influence or predict adolescents' compliance to treatment within an interdisciplinary pediatric chronic pain management program. Participants included 64 adolescents ( = 15.00 ± 1.69 years); 85.9% female, 84.4% Caucasian who presented to an initial evaluation in an interdisciplinary pediatric pain management program with their caregiver. Youth completed a series of questionnaires at the initial evaluation targeting pain acceptance, self-efficacy, pain catastrophizing, parental responses, pain intensity, and functional disability. Treatment compliance was measured at 3 and 6 months post-intake. Findings indicated that higher levels of adolescent-reported self-efficacy predict decreased treatment session attendance, whereas lower levels of acceptance and parental encouragement/monitoring of symptoms predict increased treatment compliance overall. Several adolescent-reported risk factors were associated with increased functional impairment among this sample. Results highlight the unique importance of risk and resilience factors within the developmental context of adolescence, while also emphasizing the need for further investigation of other relevant influences towards treatment compliance and functional impairment.

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OnabotulinumtoxinA.

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The Process of Creating and Disseminating Exercise Programs by Physical Therapists for Older Adults With Chronic Back Pain.

The purpose of this study was to enhance the understanding of the process that physical therapists undertake when creating and disseminating exercise programs for older adults with chronic back pain.

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Nonopioid GTS-21 Mitigates Burn Injury Pain in Rats by Decreasing Spinal Cord Inflammatory Responses.

Burn injury (BI) pain consists of inflammatory and neuropathic components and activates microglia. Nicotinic alpha 7 acetylcholine receptors (α7AChRs) expressed in microglia exhibit immunomodulatory activity during agonist stimulation. Efficacy of selective α7AChR agonist GTS-21 to mitigate BI pain and spinal pain-mediators was tested.

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Barriers and facilitators to implementing changes in opioid prescribing in rural primary care clinics.

Opioids are more commonly prescribed for chronic pain in rural settings in the USA, yet little is known about how the rural context influences efforts to improve opioid medication management.

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High Prevalence of Perineural Cysts in Patients with Fibromyalgia and Chronic Fatigue Syndrome.

Pain in fibromyalgia (FM) and chronic fatigue syndrome (CFS) is assumed to originate from central sensitization. Perineural cysts or Tarlov cysts (TCs) are nerve root dilations resulting from pathologically increased cerebrospinal fluid pressure. These cysts initially affect sensory neurons and axons in dorsal root ganglia and produce sensory symptoms (pain and paresthesia). Symptomatic TC (STC) patients often complain about widespread pain and fatigue. Consequently, STC patients may initially be diagnosed with FM, CFS, or both. The objective of this study was to document the prevalence of TCs in patients diagnosed with FM or CFS.

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Phenotypes of Women with and Without Endometriosis and Relationship with Functional Pain Disability.

Primary dysmenorrhea and secondary dysmenorrhea due to endometriosis share overlapping symptoms and likely demonstrate aspects of central sensitization. The present study aimed to identify distinct phenotypes of women who have dysmenorrhea with and without endometriosis to shed light on the unique mechanisms contributing to the pathogenesis of each condition.

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Pathogenic mechanisms of lipid mediator lysophosphatidic acid in chronic pain.

A number of membrane lipid-derived mediators play pivotal roles in the initiation, maintenance, and regulation of various types of acute and chronic pain. Acute pain, comprising nociceptive and inflammatory pain warns us about the presence of damage or harmful stimuli. However, it can be efficiently reversed by opioid analgesics and anti-inflammatory drugs. Prostaglandin E and I, the representative lipid mediators, are well-known causes of acute pain. However, some lipid mediators such as lipoxins, resolvins or endocannabinoids suppress acute pain. Various types of peripheral and central neuropathic pain (NeuP) as well as fibromyalgia (FM) are representatives of chronic pain and refractory owing to abnormal pain processing distinct from acute pain. Accumulating evidence demonstrated that lipid mediators represented by lysophosphatidic acid (LPA) are involved in the initiation and maintenance of both NeuP and FM in experimental animal models. The LPAR-mediated peripheral mechanisms including dorsal root demyelination, Caα2δ1 expression in dorsal root ganglion, and LPAR-mediated amplification of central LPA production via glial cells are involved in the series of molecular mechanisms underlying NeuP. This review also discusses the involvement of lipid mediators in emerging research directives, including itch-sensing, sexual dimorphism, and the peripheral immune system.

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Effects of Mindfulness-Based Stress Reduction on Experimental Pain Sensitivity and Cortisol Responses in Women with Early Life Abuse: A Randomized Controlled Trial.

Early life abuse (ELAb) initiates pathophysiological cascades resulting in long-term maladaptive stress responsivity, hyperalgesia and an increased risk for psychopathology. Mindfulness-based stress reduction (MBSR) is effective in modifying psychological and somatic symptoms; thus, we predicted that MBSR would be particularly efficacious for women with ELAb.

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Chasing the Dragon: Driving the Paradigm Shift to Move Beyond Opioids.

The opioid crisis is more severe in the United States than in any other country. This may be due, in part, to a cultural problem related to pain: Americans have come to expect quick, easy, physician-provided pain relief. Pharmaceuticals can neither cure injuries nor correct the underlying cause of any chronic musculoskeletal condition. Fortunately, people who regularly exercise have less pain, and guidelines for the management of painful chronic conditions already recommend exercise therapies over passive care. This suggests that self-care approaches emphasizing exercise are the logical, lowest-cost, first-line treatment. For patients who require guidance with exercise, the stepped-care approach to pain management commonly taught in medical school curricula should include guided physical rehabilitation early, if not first. This has been shown to be associated with fewer high-cost services and less opioid medication. Keeping people opioid naïve, when appropriate, could save tens of thousands of American lives annually and many more globally. Attitudes, behaviors, and policies must evolve to shed the culture of first-line pharmaceutical pain management. .

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Pain sensitivity is reduced by exercise training: Evidence from a systematic review and meta-analysis.

BELAVY, D. L., J. Van Oosterwijck, M. Clarkson, E. Dhondt, N. L. Mundell, C. Miller and P. J. Owen. NEUROSCI BIOBEHAV REV 21(1) XXX-XXX, 2020. Exercise training is capable of reducing pain in chronic pain syndromes, yet its mechanisms are less well established. One mechanism may be via the impact of exercise on increasing a person's pain threshold. Here we show, via meta-analysis of fifteen exercise training studies in pain syndromes that exercise training leads to increased pressure pain thresholds (low to moderate quality evidence). We also find low to moderate quality evidence exists that exercise training was more effective than non-exercise interventions, such as pain education, massage and stress management for improving pain sensitivity. Further, the effect of exercise was greater locally at the site of pain and less so at remote regions. These finding suggest that adaptations in central inhibition occur over time with exercise training and, more widely, add to the mechanistic understanding of how effective interventions can improve pain in chronic pain syndromes.

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Using visual feedback manipulation in virtual reality to influence pain-free range of motion in people with non-specific neck pain.

Based on associative learning theories it is hypothesised that pain might be a conditioned response. In people with musculoskeletal pain, the occurrence of movement-induced pain might be a protective response, influenced by visual cues suggesting that the person is approaching a painful position. This study aimed to determine (1) whether pain-free range of motion (ROM) increased and decreased when visual feedback understated or overstated true rotation in people with neck pain and (2) whether this effect was more pronounced if pain was chronic.

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Behavioral Activation and Inhibition Systems: Further Evaluation of a BIS-BAS Model of Chronic Pain.

The role of the behavioral inhibition system (BIS) and behavioral activation system (BAS) in function has been evaluated in a wide range of populations. However, research on the role of the BIS and BAS in pain is in its early stages. This study sought to evaluate the utility of a BIS-BAS model of chronic pain.

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Activation of Trace Amine-Associated Receptor 1 Selectively Attenuates the Reinforcing Effects of Morphine.

Trace amine-associated receptor 1 (TAAR1) plays a critical role in regulating dopamine transmission. Previous studies showed that pharmacologically or genetically manipulating the activity of TAAR1 modulates addiction-like behaviors associated with psychostimulants. However, little is known about whether TAAR1 modulation would regulate the behavioral effects of opioids.

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Ion Channels and Transporters in Microglial Function in Physiology and Brain Diseases.

Microglial cells interact with all components of the central nervous system (CNS) and are increasingly recognized to play essential roles during brain development, homeostasis and disease pathologies. Functions of microglia include maintaining tissue integrity, clearing cellular debris and dead neurons through the process of phagocytosis, and providing tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. Changes of microglial ionic homeostasis (Na, Ca, K, H, Cl) are important for microglial activation, including proliferation, migration, cytokine release and reactive oxygen species production, etc. These are mediated by ion channels and ion transporters in microglial cells. Here, we review the current knowledge about the role of major microglial ion channels and transporters, including several types of Ca channels (store-operated Ca entry (SOCE) channels, transient receptor potential (TRP) channels and voltage-gated Ca channels (VGCCs)) and Na channels (voltage-gated Na channels (Nav) and acid-sensing ion channels (ASICs)), K channels (inward rectifier K channels (K), voltage-gated K channels (K) and calcium-activated K channels (K)), proton channels (voltage-gated proton channel (Hv1)), and Cl channels (volume (or swelling)-regulated Cl channels (VRCCs) and chloride intracellular channels (CLICs)). In addition, ion transporter proteins such as Na/Ca exchanger (NCX), Na-K-Cl cotransporter (NKCC1), and Na/H exchanger (NHE1) are also involved in microglial function in physiology and brain diseases. We discussed microglial activation and neuroinflammation in relation to the ion channel/transporter stimulation under brain disease conditions and therapeutic aspects of targeting microglial ion channels/transporters for neurodegenerative disease, ischemic stroke, traumatic brain injury and neuropathic pain.

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Association Between Multimorbid Disease Patterns and Pain Outcomes Among a Complex Chronic Care Population in Canada.

Disease multimorbidity and pain is a complex, yet common, problem for the aging population, and a significant burden on the health-care systems around the world. Despite this, disease comorbidity and the association with pain in a complex chronic care population is not well understood. This study examined the most prevalent disease combinations and their association with pain.

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Recently available and emerging therapeutic strategies for the acute and prophylactic management of cluster headache: a systematic review and expert opinion.

: Although it causes a huge burden to sufferers, cluster headache (CH), remains an undertreated condition, partly due to the absence of established acute and prophylactic treatment options. New therapeutic approaches providing fast and safe relief from CH are needed. : A systematic review was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendation on recently published (last 5 years) papers on CH treatment. The authors also collected preliminary results from ongoing trials on emerging therapeutic/preventive pharmacological and interventional approaches for CH. Studies and results are reviewed and discussed. : The complexity of CH pathophysiology prevents the definition of reliable acute and preventive treatments. In the real-world clinical setting, several treatments are combined to provide relief to patients and increase their quality of life. Drugs targeting neuropeptides or their receptors within the trigeminovascular network are of particular interest to prevent CH attacks. Calcitonin gene-related peptide (CGRP) blockade seems attractive and promising, but studies on anti-CGRP monoclonal antibodies indicated rather modest or even absence of a prophylactic effect. A deeper insight into CH pathophysiology, and combined approaches may lead the path to new, more effective and personalized CH therapies.

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αCGRP-Induced Changes in Cerebral and Systemic Circulation; A TCD Study.

It is known that perivascular application of CGRP induces cerebral vasodilatation. However, it is unclear whether intravenous alfa CGRP (αCGRP) induces changes in cerebral and systemic hemodynamics. Therefore, we studied the influence of an αCGRP intravenous infusion at a rate of 1.5 mcg/min in 20 min on mean arterial velocity in the middle cerebral artery (vm MCA) and in the posterior cerebral artery (vm PCA) in twenty healthy subjects using transcranial Doppler (TCD). We found out that αCGRP decreased vm MCA ( < 0.001), vm PCA ( < 0.001), mean arterial pressure (MAP) ( < 0.001) and end-tidal CO (Et-CO) ( = 0.030). The heart rate (HR) increased during αCGRP infusion ( < 0.001). In addition, we found a positive relationship between Et-CO and vm MCA ( = 0.001) as well as vm PCA ( = 0.043). In our view, αCGRP induces changes in cerebral and systemic circulation in healthy volunteers. It might cause vasodilatation of MCA and PCA and a compensatory decrease of Et-CO to αCGRP related hemodynamic changes.

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The Effectiveness of Dorsal Root Ganglion Neurostimulation for the Treatment of Chronic Pelvic Pain and Chronic Neuropathic Pain of the Lower Extremity: A Comprehensive Review of the Published Data.

To evaluate the effectiveness of dorsal root ganglion neurostimulation for the treatment of refractory, focal pain in the pelvis and lower extremities.

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Hedging against Neuropathic Pain: Role of Hedgehog Signaling in Pathological Nerve Healing.

The peripheral nervous system has important regenerative capacities that regulate and restore peripheral nerve homeostasis. Following peripheral nerve injury, the nerve undergoes a highly regulated degeneration and regeneration process called Wallerian degeneration, where numerous cell populations interact to allow proper nerve healing. Recent studies have evidenced the prominent role of morphogenetic Hedgehog signaling pathway and its main effectors, Sonic Hedgehog (SHH) and Desert Hedgehog (DHH) in the regenerative drive following nerve injury. Furthermore, dysfunctional regeneration and/or dysfunctional Hedgehog signaling participate in the development of chronic neuropathic pain that sometimes accompanies nerve healing in the clinical context. Understanding the implications of this key signaling pathway could provide exciting new perspectives for future research on peripheral nerve healing.

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Long noncoding RNA GAS5 ameliorates chronic constriction injury induced neuropathic pain in rats by modulation of the miR-452-5p/CELF2 axis.

Neuropathic pain is a type of spontaneous pain that causes damage to the central nervous system. Long noncoding RNAs (lncRNAs) participate in the progression of various nervous system diseases, including neuropathic pain. However, the biological function of GAS5 in neuropathic pain remains unclear. Our findings revealed that GAS5 was downregulated in chronic constriction injury (CCI) rats. Besides, ELISA showed that the concentration of IL-6, TNF-α, and IL-1β were reduced by overexpressed GAS5 in spinal cord homogenates of CCI rats. Moreover, mechanical allodynia and thermal hyperalgesia in CCI rats were inhibited by GAS5 overexpression, suggesting that GAS5 overexpression attenuated neuropathic pain. Subsequently, we found that GAS5 served as a sponge for miR-452-5p in CCI rats and CELF2 was the downstream target of miR-452-5p. Finally, through a rescue assay, we found that GAS5 ameliorated neuropathic pain in CCI rats by sponging miR-452-5p to regulate CELF2 expression. Our study confirmed that GAS5 ameliorated neuropathic pain in rats by modulation of the miR-452-5p/CELF2 axis, which may provide some clues for neuropathic pain treatment.

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Selective Ablation of Descending Serotonin from the Rostral Ventromedial Medulla Unmasks Its Pro-Nociceptive Role in Chemotherapy-Induced Painful Neuropathy.

Chemotherapy-induced painful neuropathy (CIPN) is a severe adverse effect of many anti-neoplastic drugs that is difficult to manage. Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter in the rostral ventromedial medulla (RVM), which modulates descending spinal nociceptive transmission. However, the influence of the descending 5-HT from the RVM on CIPN is poorly understood. We investigated the role of 5-HT released from descending RVM neurons in a paclitaxel-induced CIPN rat model.

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Drugs for chronic pain.

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Identification of a Potent and Selective 5-HT Receptor Agonist with and Antinociceptive Activity.

Opioids are the gold standard drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HTR agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HTR agonists -[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate () and -((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate () and . The role of chirality in the interaction with 5-HTR was evaluated by molecular docking. The activity of the was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). was active in the formalin test with a reduction in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HTR antagonist, WAY-100635. The eutomer ()-, but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, ()- evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than -. The eutomer ()- showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the μ receptors, and low hepato- and cardiotoxicity. Therefore, ()- may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly associated with the classic opioid drugs.

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Treatment of Neck Pain with Opioids in the Primary Care Setting: Trends and Geographic Variation.

Neck pain is a leading cause of years lived with disability and is often managed with opioid medications in primary care settings, though this is contraindicated by national guidelines. The aim of this study was to determine the prevalence of opioid prescription for neck pain at a primary care visit and to analyze the geographic variation and trends in opioid prescriptions between 2011 and 2017.

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Sensory neuron cultures derived from adult db/db mice as a simplified model to study type-2 diabetes-associated axonal regeneration defects.

Diabetic neuropathy (DN) is an early, common complication of diabetes mellitus (DM) leading to chronic pain, sensory loss and muscle atrophy. Due to its multifactorial etiology, neuron cultures have been proposed as simplified systems for DN studies. However, the most used models currently available do not recreate the chronic and systemic damage suffered by peripheral neurons of type-2 DM (T2DM) individuals. Here, we cultured neurons derived from dorsal root ganglia from 6-month-old diabetic db/db-mice, and evaluated their morphology by the Sholl method as an easy-to-analyze readout of neuronal function. We showed that neurons obtained from diabetic mice exhibited neuritic regeneration defects in basal culture conditions, compared to neurons from non-diabetic mice. Next, we evaluated the morphological response to common neuritogenic factors including NGF and laminin. Neurons derived from diabetic mice exhibited reduced regenerative responses to these factors compared to neurons from non-diabetic mice. Finally, we analyzed the neuronal response to a putative DN therapy based on the secretome of mesenchymal stem cells (MSC). Neurons from diabetic mice treated with MSC-secretome displayed a significant improvement in neuritic regeneration, but still reduced when compared to neurons derived from non-diabetic mice. This model recapitulates many alterations observed in sensory neurons of T2DM individuals, suggesting the possibility of studying neuronal functions without the need of adding additional toxic factors to culture plates. This model may be useful for evaluating intrinsic neuronal responses in a cell-autonomous manner, and as a throughput screening for the pre-evaluation of new therapies for DN.

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Inflammatory mediators in the pronociceptive effects induced by Bothrops leucurus snake venom: the role of biogenic amines, nitric oxide, and eicosanoids.

Bothrops leucurus is the major causative agent of venomous snakebites in Northeastern Brazil. Severe pain is the most frequent symptom in these envenomings, with an important inflammatory component. This work characterized the pronociceptive effects evoked by B. leucurus venom (BLV) in mice and the role of inflammatory mediators in these responses. The nociceptive behaviors were quantified by the modified formalin test. The mechanical hyperalgesia was assessed by the digital von Frey test. Pharmacological assays were performed with different antagonists and synthesis inhibitors to investigate the involvement of inflammatory mediators in both nociceptive events. BLV (1 – 15 µg/paw) injection in mice evoked intense and dose-dependent nociceptive behaviors that lasted for up to 1 h. BLV (10 µg/paw) also caused sustained mechanical hyperalgesia. Histamine and serotonin played a role in the nociception, but not in the BLV-induced mechanical hyperalgesia. Nitric oxide contributed to both responses, but only to the late stages of mechanical hyperalgesia. Eicosanoids were also present in both nociceptive responses. Prostanoid synthesis by COX-1 seemed to be more relevant for the nociception, whereas COX-2 had a more prominent role in the mechanical hyperalgesia. Leukotrienes were the most relevant mediators of BLV-induced mechanical hyperalgesia, hence inhibiting lipoxygenase pathway could be an efficient therapeutic strategy for pain management during envenoming. Our behavioral data demonstrates that BLV promotes nociceptive transmission mediated by biogenic amines, nitric oxide and eicosanoids, and nociceptor sensitization through nitric oxide and eicosanoids. Moreover, phospholipases A (PLA), an important class of toxins present in bothropic venoms, appear to play an important role in the nociceptive and hypernociceptive response induced by BLV.

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Association between patient independence in performing an exercise program and adherence to home exercise program in people with chronic low back pain.

A high percentage of patients with chronic low back pain (LBP) do not adequately adhere to home exercise programs. There is no information regarding a possible association between patient independence in performing an exercise program and adherence to this exercise program.

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Drug-Nutraceutical Co-Crystal and Salts for Making New and Improved Bi-Functional Analgesics.

The discovery and development of effective analgesics is greatly lagging behind the steadily rising prevalence of chronic pain. Currently prescribed analgesics for chronic pain are lacking in efficacy mainly due to their narrowly-targeted mechanism of action. Driving neuronal hyperexcitability that underlies symptoms of chronic pain are multiple non-neuronal processes, among which are tissue hypoxia and oxidative stress. Here we demonstrate the design, synthesis, and activity of new multi-component bi-functional analgesic crystalline solids, co-crystals, and salts, based on pairing of vasodilatory anti-hypoxic drugs pentoxifylline, clonidine and linsidomine with antioxidant nutraceuticals protocatechuic acid, α-lipoic acid, and caffeic acid. After validation, chemical and structural characterization of these novel salts and co-crystals, topical formulations of the products were tested in a rat model of complex regional pain syndrome. Analgesic effects achieved with the salts and co-crystal exceeded the efficacy and/or potency of constituent compounds indicating that more effective, advanced analgesics can readily be developed by careful pairing of compounds that simultaneously target multiple neural and non-neural processes driving chronic pain.

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TRPV1 Channel: A Noxious Signal Transducer That Affects Mitochondrial Function.

The Transient Receptor Vanilloid 1 (TRPV1) or capsaicin receptor is a nonselective cation channel, which is abundantly expressed in nociceptors. This channel is an important transducer of several noxious stimuli, having a pivotal role in pain development. Several TRPV1 studies have focused on understanding its structure and function, as well as on the identification of compounds that regulate its activity. The intracellular roles of these channels have also been explored, highlighting TRPV1's actions in the homeostasis of Ca in organelles such as the mitochondria. These studies have evidenced how the activation of TRPV1 affects mitochondrial functions and how this organelle can regulate TRPV1-mediated nociception. The close relationship between this channel and mitochondria has been determined in neuronal and non-neuronal cells, demonstrating that TRPV1 activation strongly impacts on cell physiology. This review focuses on describing experimental evidence showing that TRPV1 influences mitochondrial function.

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To Trial or Not to Trial Before Spinal Cord Stimulation for Chronic Neuropathic Pain: The Patients’ View From the TRIAL-STIM Randomized Controlled Trial.

Objectives Spinal cord stimulation (SCS) is an established treatment of chronic neuropathic pain. Although a temporary SCS screening trial is widely used to determine suitability for a permanent implant, its evidence base is limited. The recent TRIAL-STIM study (a randomized controlled trial at three centers in the United Kingdom) found no evidence that an SCS screening trial strategy provides superior patient outcomes as compared with a no trial approach. As part of the TRIAL-STIM study, we undertook a nested qualitative study to ascertain patients' preferences in relation to undergoing a screening trial or not. Materials and Methods We interviewed 31 patients sampled from all three centers and both study arms (screening trial/no trial) prior to SCS implantation, and 23 of these patients again following implantation (eight patients were lost to follow-up). Interviews were undertaken by telephone and audio-recorded, then transcripts were subject to thematic analysis. In addition, participants were asked to state their overall preference for a one-stage (no screening trial) versus two-stage (screening trial) implant procedure on a five-point Likert scale, before and after implantation. Results Emergent themes favoured the option for a one-stage SCS procedure. Themes identified include: saving time (off work, in hospital, attending appointments), avoiding the worry about having "loose wires" in the two-stage procedure, having only one period of recovery, and saving NHS resources. Participants' rated preferences show similar support for a one-stage procedure without a screening trial. Conclusions Our findings indicate an overwhelming preference among participants for a one-stage SCS procedure both before and after the implant, regardless of which procedure they had undergone. The qualitative study findings further support the TRIAL-STIM RCT results.

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2-Bromopalmitate attenuates inflammatory pain by maintaining mitochondrial fission/fusion balance and function.

Inflammatory pain activates astrocytes and increases inflammatory cytokine release in the spinal cord. Mitochondrial fusion and fission rely on the functions of dynamin-related protein 1 (Drp1) and optic atrophy 1 (OPA1), which are essential for the synaptic transmission and plasticity. In the present study, we aimed to explore the effects of 2-bromopalmitate (2-BP), an inhibitor of protein palmitoylation, on the modulation of pain behavior. Rats were intraplantar injected with complete Freund's adjuvant (CFA) to establish an inflammatory pain model. In the spinal cord of rats with CFA-induced inflammatory pain, the expression of astrocyte-specific glial fibrillary acidic protein (GFAP) and contents of proinflammatory cytokines IL-1β and TNF-α were increased. Mitochondrial Drp1 was increased, while OPA1 was decreased. Consequently, CFA induced reactive oxygen species (ROS) production and Bcl-2-associated X protein (BAX) expression. The intrathecal administration of 2-BP significantly reversed the pain behaviors of the inflammatory pain in rats. Moreover, 2-BP also reduced the Drp1 expression, elevated the OPA1 expression, and further reduced the GFAP, IL-1β, and TNF-α expression and ROS production. Furthermore, in vitro study proved a similar effect of 2-BP on the regulation of Drp1 and OPA1 expression. 2-BP also increased the mitochondrial membrane potential and decreased the levels of BAX, ROS, and proinflammatory cytokines. These results indicate that 2-BP may attenuate the inflammatory pain of CFA-treated rats via regulating mitochondrial fission/fusion balance and function.

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Chronic Musculoskeletal Pain and Chronic Widespread Pain in Chile: Prevalence Study Performed as Part of the National Health Survey.

Chronic musculoskeletal pain (CMP) causes significant health loss worldwide. Given that cultural factors may affect pain processing, it is key to have more information regarding CMP epidemiology in Latin America. In this study, we aimed to determine the prevalence of CMP and chronic widespread pain (CWP) in Chile.

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Sex-specific Differences in Multisite Pain Presentation among Adults with Lower-Limb Loss.

Multisite pain remains significantly understudied following lower-limb loss (LLL), especially among females. This study aimed to explore sex-specific differences in the presentation of multisite pain post-LLL. Hypotheses were multisite pain would be more prevalent among females post-LLL as compared to males, and female sex would be significantly associated with multisite pain prevalence.

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Non-invasive brain stimulation as a tool to decrease chronic pain in current opiate users: A parametric evaluation of two promising cortical targets.

Poorly controlled chronic pain can lead to non-prescription use of opiates, which is a growing crisis in our communities. Transcranial magnetic stimulation (TMS) is a non-invasive therapeutic tool which has emerged as a potential treatment option for these patients. It is still unclear, however, if the dorsolateral prefrontal cortex (DLPFC) or the motor cortex (MC) is a more effective treatment location. The purpose of this study was to directly compare the effects of DLPFC versus MC TMS on pain severity and the urge to use opiates among chronic pain patients.

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Consensus-Based Recommendations for Titrating Cannabinoids and Tapering Opioids for Chronic Pain Control.

Opioid misuse and overuse has contributed to a widespread overdose crisis and many patients and physicians are considering medical cannabis to support opioid tapering and chronic pain control. Using a five-step modified Delphi process, we aimed to develop consensus-based recommendations on: 1) when and how to safely initiate and titrate cannabinoids in the presence of opioids, 2) when and how to safely taper opioids in the presence of cannabinoids, and 3) how to monitor patients and evaluate outcomes when treating with opioids and cannabinoids.

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Blood Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate as Pathophysiological Correlates of Chronic Pain: Analyses Using a National Sample of Midlife Adults in the United States.

Identifying biomarkers is a priority in translational chronic pain research. Dehydroepiandrosterone (DHEA) and its sulfated form, DHEA-S, are adrenocortical steroids in the blood with neuroprotective properties that also produce sex hormones. They may capture key sex-specific neuroendocrine mechanisms of chronic pain.

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Trends in Clinical Trials for Spinal Cord Stimulation.

Spinal cord stimulation (SCS) is a neuromodulation technology widely used in the treatment of intractable chronic pain syndromes. SCS is now being applied more broadly as a possible therapy for a range of indications, including neurological, cardiac, and gastrointestinal disorders. Ongoing research in this field is critical in order to gain further insights into the mechanisms of SCS, determine its role in new indications, and refine programming techniques for the optimization of therapeutic outcomes.

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Psychopharmacological characterization of an emerging drug of abuse, a synthetic opioid U-47700, in adult zebrafish.

3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a selective μ-opioid receptor agonist originally synthesized as a prospective analgesic drug. Several times more potent than morphine, U-47700 has high abuse potential and may cause clinical neurotoxicity, euphoria, respiratory depression and occasional mortality. U-47700 also evokes analgesia, sedation and euphoria-like states in both humans and rodents. Despite the growing use and abuse of U-47700, its psychopharmacological and toxicological profiles remain poorly understood. The zebrafish (Danio rerio) is rapidly becoming a popular aquatic model organism for CNS disease modeling and drug discovery. Here, we examine acute (1, 5, 10, 25 and 50 mg/L for 20-min) and chronic (0.1, 0.5 and 1 mg/L for 14 days) effects of U-47700 in adult zebrafish. Overall, we found overt sedation by acute, and hyperlocomotion with an anxiolytic-like action by chronic, drug treatments. Acute treatment with 1 and 10 mg/L U-47700 also resulted in detectable amounts of this drug in the brain samples. Collectively, these findings emphasize a complex dose- and treatment-dependent CNS profile of U-47700 following its acute and chronic administration. Our study also supports high sensitivity of zebrafish to U-47700, and suggests these aquatic models as promising in-vivo screens for probing CNS effects evoked by novel synthetic opioid drugs.

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Increasing system-wide implementation of opioid prescribing guidelines in primary care: findings from a non-randomized stepped-wedge quality improvement project.

Clinician utilization of practice guidelines can reduce inappropriate opioid prescribing and harm in chronic non-cancer pain; yet, implementation of "opioid guidelines" is subpar. We hypothesized that a multi-component quality improvement (QI) augmentation of "routine" system-level implementation efforts would increase clinician adherence to the opioid guideline-driven policy recommendations.

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Position Paper on Post-Traumatic Headache: The Relationship Between Head Trauma, Stress Disorder, and Migraine.

Traumatic brain injury (mTBI) is a major public health concern, with mild TBI (mTBI) constituting the vast majority of the injuries. Post-traumatic headache (PTH) is one of the most frequent symptoms that follow a mTBI, occurring in isolation with a tension-type or migraine phenotype, or more often as part of a complex neurobehavioural array of symptoms. The existence of PTH as a separate entity from the primary headaches is still a matter of debate. Classification issues and a lack of methodologically robust epidemiological and clinical studies have made it difficult to elucidate the mechanisms underlying acute and even more persistent PTH (PPTH). Furthermore, psychiatric comorbidities such as post-traumatic stress disorder (PTSD), previous history of migraine, and legal issues often reported by PPTH patients have complicated the understanding of this condition, hence treatment approaches for PTH remain problematic. Recent findings from structural and functional neuroimaging studies have attempted to describe the brain architecture of PPTH, suggesting the involvement of different networks compared to migraine. It also seems that calcitonin gene-related peptide (CGRP) levels are not particularly raised in PPTH, although CGRP monoclonal antibodies have obtained positive initial open-label evidence of efficacy in PPTH, and more trials assessing the efficacy of this class of treatments are underway. The broad overlap between PTH, migraine, and PTSD suggests that research in this field should start with a re-appraisal of the diagnostic criteria, followed by methodologically sound epidemiological and clinical studies. Preclinical research should strive to create more reliable PTH models to support human neuroimaging, neurochemical, and neurogenetic studies, aiming to underpin new pathophysiological hypotheses that may expand treatment targets and improve the management of PTH patients.

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Effects of magnesium sulfate administration in attenuating chronic postsurgical pain in rats.

Chronic postsurgical pain (CPSP) is a serious issue for many postoperative patients. Though there are numerous treatment options for the prevention of CPSP, none of them is optimal as the mechanisms of the transition from acute to chronic postoperative pain have not been elucidated. Ketamine and opioids have been administered for chronic postoperative pain treatment but induce severe adverse reactions and/or physical dependency. Here, we examined whether pre-administration of the nonselective N-methyl-d-aspartate (NMDA) receptor antagonist magnesium sulfate attenuates CPSP behavior and alters the expression of glutamate ionotropic receptor NMDA type subunit 1a (Grin1 mRNA) in a rat skin/muscle incision and retraction (SMIR) model. We assessed the effects of a single subcutaneous magnesium sulfate injection on nociceptive behaviors including guarding pain, mechanical hyperalgesia, and heat hypersensitivity in rats after SMIR surgery. We used reverse transcription-quantitative PCR (RT-qPCR) to evaluate Grin1 mRNA expression in the dorsal horn of the spinal cord on postoperative day 14. Compared with the vehicle, magnesium sulfate administration before SMIR surgery reduced mechanical hyperalgesia for 17 d Grin1 gene expression was significantly higher on the ipsilateral side than the contralateral side (P = 0.001) on postoperative day 14. The magnesium sulfate injection prevented Grin1 mRNA upregulation in the spinal cord dorsal horn. A single magnesium sulfate injection mitigated SMIR-induced mechanical hyperalgesia possibly by modulating Grin1 expression. Preoperative magnesium sulfate administration could prove to be a simple and safe CPSP treatment.

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Chronic back pain in first-degree relatives (FDRs) of patients with ankylosing spondylitis: predictive value of HLA-B27 and persistence of inflammatory back pain over time.

First-degree relatives (FDRs) of patients with ankylosing spondylitis (AS) may be at high risk of spondyloarthritis. We examined the frequency, characteristics of chronic back pain (CBP), associated features, persistence of symptoms, and HLA-B27 allele frequency in FDRs of AS patients, also comparing those FDRs with participants in NHANES 2009-2010 with CBP.

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Antinociception mechanisms of action of cannabinoid-based medicine: an overview for anesthesiologists and pain physicians.

Cannabinoid-based medications possess unique multimodal analgesic mechanisms of action, modulating diverse pain targets. Cannabinoids are classified based on their origin into three categories: endocannabinoids (present endogenously in human tissues), phytocannabinoids (plant derived) and synthetic cannabinoids (pharmaceutical). Cannabinoids exert an analgesic effect, peculiarly in hyperalgesia, neuropathic pain and inflammatory states. Endocannabinoids are released on demand from postsynaptic terminals and travels retrograde to stimulate cannabinoids receptors on presynaptic terminals, inhibiting the release of excitatory neurotransmitters. Cannabinoids (endogenous and phytocannabinoids) produce analgesia by interacting with cannabinoids receptors type 1 and 2 (CB1 and CB2), as well as putative non-CB1/CB2 receptors; G protein-coupled receptor 55, and transient receptor potential vanilloid type-1. Moreover, they modulate multiple peripheral, spinal and supraspinal nociception pathways. Cannabinoids-opioids cross-modulation and synergy contribute significantly to tolerance and antinociceptive effects of cannabinoids. This narrative review evaluates cannabinoids' diverse mechanisms of action as it pertains to nociception modulation relevant to the practice of anesthesiologists and pain medicine physicians.

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Cannabidiol for Pain Treatment: Focus on Pharmacology and Mechanism of Action.

Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two components found in the highest concentrations. CBD itself does not produce typical behavioral cannabimimetic effects and was thought not to be responsible for psychotropic effects of cannabis. Numerous anecdotal findings testify to the therapeutic effects of CBD, which in some cases were further supported by research findings. However, data regarding CBD's mechanism of action and therapeutic potential are abundant and omnifarious. Therefore, we review the basic research regarding molecular mechanism of CBD's action with particular focus on its analgesic potential. Moreover, this article describes the detailed analgesic and anti-inflammatory effects of CBD in various models, including neuropathic pain, inflammatory pain, osteoarthritis and others. The dose and route of the administration-dependent effect of CBD, on the reduction in pain, hyperalgesia or allodynia, as well as the production of pro and anti-inflammatory cytokines, were described depending on the disease model. The clinical applications of CBD-containing drugs are also mentioned. The data presented herein unravel what is known about CBD's pharmacodynamics and analgesic effects to provide the reader with current state-of-art knowledge regarding CBD's action and future perspectives for research.

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