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Calcitonin-gene-related peptide (CGRP) plays a key role in migraine pathophysiology. Aimovig (erenumab; erenumab-aooe in the United States) is the only US Food and Drug Administration (FDA)-approved monoclonal antibody (mAb) therapy against the CGRP receptor (CGRPR) for the prevention of migraine. Aimovig is also the first FDA-approved mAb against a G-protein-coupled receptor (GPCR). Here, we report the architecture and functional attributes of erenumab critical for its potent antagonism against CGRPR. The crystal structure of erenumab in complex with CGRPR reveals a direct ligand-blocking mechanism, enabled by a remarkable 21-residue-long complementary determining region (CDR)-H3 loop, which adopts a tyrosine-rich helix-turn tip and projects into the deep interface of the calcitonin receptor-like receptor (CLR) and RAMP1 subunits of CGRPR. Furthermore, erenumab engages with residues specific to CLR and RAMP1, providing the molecular basis for its exquisite selectivity. Such structural insights reveal the drug action mechanism of erenumab and shed light on developing antibody therapeutics targeting GPCRs.
Learn More >The pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1R) belongs to the secretin receptor family and is widely distributed in the central neural system and peripheral organs. Abnormal activation of the receptor mediates trigeminovascular activation and sensitization, which is highly related to migraine, making PAC1R a potential therapeutic target. Elucidation of PAC1R activation mechanism would benefit discovery of therapeutic drugs for neuronal disorders. PAC1R activity is governed by pituitary adenylate cyclase-activating polypeptide (PACAP), known as a major vasodilator neuropeptide, and maxadilan, a native peptide from the sand fly, which is also capable of activating the receptor with similar potency. These peptide ligands have divergent sequences yet initiate convergent PAC1R activity. It is of interest to understand the mechanism of PAC1R ligand recognition and receptor activity regulation through structural biology. Here we report two near-atomic resolution cryo-EM structures of PAC1R activated by PACAP38 or maxadilan, providing structural insights into two distinct ligand binding modes. The structures illustrate flexibility of the extracellular domain (ECD) for ligands with distinct conformations, where ECD accommodates ligands in different orientations while extracellular loop 1 (ECL1) protrudes to further anchor the ligand bound in the orthosteric site. By structure-guided molecular modeling and mutagenesis, we tested residues in the ligand-binding pockets and identified clusters of residues that are critical for receptor activity. The structures reported here for the first time elucidate the mechanism of specificity and flexibility of ligand recognition and binding for PAC1R, and provide insights toward the design of therapeutic molecules targeting PAC1R.
Learn More >Migraine is one of the most common neurologic disorders in children and adolescents. However, a quantitative comparison of multiple preventive pharmacologic treatments in the pediatric population is lacking.
Learn More >G protein-coupled receptors can signal through both G proteins and ß-arrestin2. For the μ-opioid receptor, early experimental evidence from a single study suggested that G protein signalling mediates analgesia whereas ß-arrestin2 signalling mediates respiratory depression and constipation. Consequently, for more than a decade much research effort has been focused on developing biased μ-opioid agonists that preferentially target G protein signalling over β-arrestin signalling as it was believed that such drugs would be analgesics devoid of respiratory depressant activity. However, the prototypical compounds that have been developed based on this concept have so far failed in clinical and preclinical development.
Learn More >Group differences in touch and pain thresholds-and their neural correlates-were studied in women with provoked vestibulodynia (PVD; N = 15), a common subtype of vulvodynia (chronic vulvar pain), and pain-free control women (N = 15). Results from quantitative sensory testing and self-report measures indicated that, as compared with control participants, women with PVD exhibited allodynia (ie, pain in response to a normally nonpainful stimulus) and hyperalgesia (ie, an increased response to a normally painful stimulus) at vulvar and nonvulvar sites. In addition, brain imaging analyses demonstrated reduced difference scores between touch and pain in the S2 area in women with PVD compared with control participants, supporting previous findings of allodynia in women with PVD. There were no significant reductions in difference scores between touch and pain for regions related to cognitive and affective processing of painful stimuli. The results of this study contribute important information to the general pain and vulvodynia literatures in elucidating the specific sensorimotor neural mechanisms that underlie hyperalgesia in a chronic pain population. These results have implications for differentiating neural processing of touch and pain for women with and without PVD. Future research should attempt to examine alterations related to hyperalgesia in commonly comorbid conditions of PVD.
Learn More >Complex regional pain syndrome (CRPS) and fibromyalgia are chronic pain conditions of unexplained origins. In addition to symptoms in the diagnostic criteria, patients can report changes to vision and other sensations or bodily functions. It is unclear whether these are greater than would be expected due to normal ageing, living with chronic pain generally, or common co-morbidities of chronic pain such as depression or anxiety. We administered an on-line survey evaluating the frequencies and types of self-reported somatic symptoms, bodily changes, and sensory sensitivity in respondents with CRPS (n=390), fibromyalgia (n=425), and both CRPS and fibromyalgia ('CRPS+fibromyalgia'; n=88) compared to respondents with other chronic pain conditions (n=331) and pain-free controls (n=441). The survey assessed somatic symptoms (Patient Health Questionnaire-15), bodily changes, pain/discomfort/distress triggers, and pain intensifiers. We conducted ANCOVA's with age, sex, Patient Health Questionnaire-9 (measuring depression), Generalized Anxiety Disorder-7, pain duration in years, hours of pain per day, and number of pain-related medical diagnoses as covariates. After controlling for covariates, respondents with CRPS and/or fibromyalgia reported more somatic symptoms, changes in movement and biological responses, pain/discomfort/distress triggers, and pain intensifiers than pain(-free) control groups. Fibromyalgia specifically related to changes in vision and hearing; urinary/intestinal function; and drinking and eating. CRPS changes related to changes in hair, skin, and nails; and infection and healing. The CRPS+fibromyalgia group presented with features of both disorders with minimal additional stressors or symptoms over and above these. Our findings suggest CRPS and fibromyalgia share underlying pathophysiologies, although specific mechanisms might be different.
Learn More >Chronic non-cancer pain (CNCP) is a significant health burden among adults. Standard behavioral therapies typically focus on targeting negative affect (NA) and yield only modest treatment effects. The aims of this study were to systematically review and investigate the association between positive affect (PA) and pain severity among adults with CNCP. Databases search included MEDLINE (PubMed), PsycINFO, CINAHL, ProQuest Dissertations and Theses, OLASTER, Open Grey, and PsyArXiv (inception to July 23, 2019). We analyzed studies that: (1) employed observational, experimental, or intervention study designs; (2) enrolled individuals with CNCP (pain ≥ 12 weeks); and (3) reported full quantitative results on outcomes. Two researchers independently screened articles, extracted data, and assessed the risk of bias. The main meta-analysis was followed by subgroup analyses. All analyses were performed using random-effects models. Formal tests for heterogeneity (Q-statistic; I) and publication bias (p-curve and p-uniform*) were performed. We meta-analyzed 29 studies with 3521 participants. Results demonstrated that PA inversely impacts pain severity in people with CNCP (r = -0.23). Subgroup analyses showed a significant effect for gender and marginally significant effects for age in studies that adjusted for NA. On average, effect sizes for observational studies were larger in studies with a higher proportion of female respondents and in studies that did not adjust for NA. Finally, larger effect sizes were found in intervention studies with older compared with younger samples.
Learn More >Altered pronociceptive and antinociceptive mechanisms are often implicated in painful conditions and have been increasingly studied over the past decade. For some painful conditions, alterations are well-established, but in populations with low back pain (LBP), there remains considerable debate whether these mechanisms are altered. The present systematic review aimed to address this issue by identifying studies assessing conditioned pain modulation (CPM) and/or temporal summation of pain (TSP) in patients with LBP, comparing with either a healthy control group or using a method with reference data available. Qualitative synthesis and quantitative meta-analysis of group differences were performed. For CPM and TSP, 20 and 29 original articles were eligible, with data for meta-analysis obtainable from 18 (1500 patients and 505 controls) and 27 (1507 patients and 1127 controls) studies, respectively. Most studies were of poor-to-fair quality with significant heterogeneity in study size, population, assessment methodology, and outcome. Nonetheless, CPM was impaired in patients with LBP compared with controls (standardized mean difference = -0.44 [-0.64 to -0.23], P < 0.001), and the magnitude of this impairment was related to pain chronicity (acute/recurrent vs chronic, P = 0.003), duration (RS = -0.62, P = 0.006), and severity (RS = -0.54, P = 0.02). Temporal summation of pain was facilitated in patients with LBP compared with controls (standardized mean difference = 0.50 [0.29-0.72], P < 0.001), and the magnitude of this facilitation was weakly related to pain severity (RS= 0.41, P = 0.04) and appeared to be influenced by test modality (P < 0.001). Impaired CPM and facilitated TSP were present in patients with LBP compared with controls, although the magnitude of differences was small which may direct future research on the clinical utility.
Learn More >Satellite glial cells (SGCs) are homeostatic cells enveloping the somata of peripheral sensory and autonomic neurons. A wide variety of neuronal stressors trigger activation of SGCs, contributing to, for example, neuropathic pain through modulation of neuronal activity. However, compared to neurons and other glial cells of the nervous system, SGCs have received modest scientific attention and very little is known about SGC biology, possibly due to the experimental challenges associated with studying them in vivo and in vitro. Utilizing a recently developed method to obtain SGC RNA from dorsal root ganglia (DRG), we took a systematic approach to characterize the SGC transcriptional fingerprint by using next-generation sequencing and, for the first time, obtain an overview of the SGC injury response. Our RNA sequencing data are easily accessible in supporting information in Excel format. They reveal that SGCs are enriched in genes related to the immune system and cell-to-cell communication. Analysis of SGC transcriptional changes in a nerve injury-paradigm reveal a differential response at 3 days versus 14 days postinjury, suggesting dynamic modulation of SGC function over time. Significant downregulation of several genes linked to cholesterol synthesis was observed at both time points. In contrast, regulation of gene clusters linked to the immune system (MHC protein complex and leukocyte migration) was mainly observed after 14 days. Finally, we demonstrate that, after nerve injury, macrophages are in closer physical proximity to both small and large DRG neurons, and that previously reported injury-induced proliferation of SGCs may, in fact, be proliferating macrophages.
Learn More >This review identified prospective cohort studies in the general population which showed incidence (23 papers) and risk factors (37 papers) for fibromyalgia and chronic widespread pain. Median incidence of physician diagnosed fibromyalgia in the general population was 4.3 per 1000 person-years [range = 0.33-18.8] but 14.0 [1.2 – 32.7] if medical illness was present. Median incidence of chronic widespread pain was 12.5 per 1000 person-years [7.2-81.6] but 67 per 1000 person years [14.8 to 124] for those with pre-existing pain. Risk factors included various childhood difficulties, female sex (except with pre-existing medical disorders) , older/middle age, smoking, high BMI, alcohol abstinence and pre-existing medical disorders in adulthood. The strongest associations were with sleep disorders, headaches and other pains, depression and illness behaviour.These data suggest strongly that there are many aetiological routes into fibromyalgia and future research could be enhanced by studying the underlying mechanisms relating to these risk factors.
Learn More >Pain alters cognitive performance through centrally mediated effects in the brain. In this study, we hypothesized that persistent activation of peripheral nociceptors after injury would lead to the development of a chronic pain state that impairs attention-related behavior and results in changes in peripheral neuron phenotypes. Attentional performance was measured in rats using the 5-choice serial reaction time titration variant to determine the initial impact of partial L5 spinal nerve ligation and the effect of persistent nociceptor activation on the resolution of injury. The changes in peripheral neuronal sensibilities and phenotypes were determined in sensory afferents using electrophysiologic signatures and receptive field properties from dorsal root ganglion recordings. Partial spinal nerve injury impaired attentional performance, and this was further impaired in a graded fashion by nociceptive input through an engineered surface. Impairment in attention persisted for only up to 4 days initially, followed by a second phase 7 to 10 weeks after injury in animals exposed to nociceptive input. In animals with prolonged impairment in behavior, the mechanonociceptors displayed a persistent hypersensitivity marked by decreased threshold, increased activity to a given stimulus, and spontaneous activity. Nerve injury disrupts attentional performance acutely and is worsened with peripheral mechanonociceptor activation. Acute impairment resolves, but persistent nociceptive activation produces re-emergence of impairment in the attention-related task associated with electrophysiological abnormalities in peripheral nociceptors. This is consistent with the development of a chronic pain state marked by cognitive impairment and related to persistently abnormal peripheral input.
Learn More >Pain and hypersensitivity months after peripheral injury reflect abnormal input from peripheral afferents likely in conjunction with central sensitization. We hypothesize that peripheral changes occur in defined sensory afferents and resolve as behavioral response to injury resolves. Male Sprague-Dawley rats underwent sham or partial L5 spinal nerve ligation, and paw withdrawal threshold (PWT) was sequentially measured during recovery. At 2, 4, 8, and 12 weeks after injury, randomized animals underwent electrophysiologic assessment of L4 fast-conducting high- and low-threshold mechanoreceptors, and individual neuronal mechanical thresholds (MTs) were contrasted with PWTs in the same animals. Paw withdrawal thresholds decreased after injury and resolved over time (P < 0.001). Similarly, MTs of fast-conducting high-threshold mechanoreceptors decreased after injury and resolved over time (P < 0.001). By contrast, MTs of low-threshold mechanoreceptors increased after injury and resolved over time (P < 0.001). Distributions of recordings from each afferent subtype were perturbed after injury, and this too resolved over time. After resolution of behavioral changes, several electrical abnormalities persisted in both neuronal subtypes. These data extend previous findings that mechanically sensitive nociceptors are sensitized, whereas tactile, largely Aβ afferents are desensitized after nerve injury by showing that the time course of resolution of these changes mirrors that of behavioral hypersensitivity in a surgical injury including neural damage. These data support a role of abnormal peripheral input, from both nociceptor and tactile afferents, during recovery from peripheral injury and underscore the potential importance of both classes of afferents as potential targets for pain treatment.
Learn More >Epidemiological and cross-sectional studies have shown that post-traumatic stress disorder symptoms (PTSS) are common and impairing in youth with chronic pain. Yet, the co-occurrence of PTSS and pediatric chronic pain has not been examined longitudinally, which has limited understanding of theoretically proposed mechanisms (eg, sleep disturbance) underlying the PTSS-pain relationship over time. This longitudinal study aimed to fill this gap. Participants included 138 youth (Mage = 14.29, 75% girls) referred to a tertiary-level outpatient chronic pain program and one of their parents. At baseline, youth reported their pain intensity and interference, PTSS, and subjective sleep disturbances (ie, sleep quality and insomnia). Youth and parents completed semistructured diagnostic interviews to determine the child's post-traumatic stress disorder diagnostic status, and youth completed an objective assessment of sleep patterns for 7 days using actigraphy. At 3-month follow-up, youth once again completed the diagnostic interview and reported their pain intensity, pain interference, and PTSS. Partially latent cross-lagged structural equation panel models revealed that, controlling for pain intensity, pain interference and PTSS co-occurred at baseline, but not at follow-up (while controlling for baseline levels). Higher levels of baseline PTSS were predictive of increases in pain interference at follow-up. Furthermore, subjective sleep disturbances mediated the relationship between baseline PTSS and follow-up pain interference. These findings lend support to conceptual models of PTSS-pain co-occurrence and highlight a critical need to assess and address trauma and sleep disturbances in youth with chronic pain.
Learn More >Chronic low back pain conditions are highly prevalent and constitute the leading cause of disability worldwide. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the US Food and Drug Administration and the American Pain Society (APS), have combined to create the ACTTION-APS Pain Taxonomy (AAPT). The AAPT initiative convened a working group to develop diagnostic criteria for chronic low back pain. The working group identified three distinct low back pain conditions which result in a vast public health burden across the lifespan. This article focuses on: 1) the axial predominant syndrome of chronic musculoskeletal low back pain, 2) the lateralized, distally-radiating syndrome of chronic lumbosacral radicular pain 3) and neurogenic claudication associated with lumbar spinal stenosis. This classification of chronic low back pain is organized according to the AAPT multidimensional framework, specifically (1) core diagnostic criteria; (2) common features; (3) common medical and psychiatric comorbidities; (4) neurobiological, psychosocial, and functional consequences; and (5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. Perspective: An evidence-based classification of chronic low back pain conditions was constructed for the AAPT initiative. This multidimensional diagnostic framework includes: (1) core diagnostic criteria; (2) common features; (3) medical and psychiatric comorbidities; (4) neurobiological, psychosocial, and functional consequences; and (5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors.
Learn More >Although migraine is defined by the headache and headache associated symptoms, the true beginning of a migraine attack lies in the premonitory phase and to understand the generation of attacks one needs to investigate the phase before headache starts. The premonitory phase of migraine is characterized by a well described complex of symptoms. Its duration, however, is not clearly defined and there are to date no biomarkers to help defining when this phase starts.
Learn More >Spinal cord microglia contribute to nerve injury-induced neuropathic pain. We have previously demonstrated that toll-like receptor 2 (TLR2) signaling is critical for nerve injury-induced activation of spinal cord microglia, but the responsible endogenous TLR2 agonist has not been identified. Here, we show that nerve injury-induced upregulation of sialyltransferase St3gal2 in sensory neurons leads to an increase in expression of the sialylated glycosphingolipid, GT1b. GT1b ganglioside is axonally transported to the spinal cord dorsal horn and contributes to characteristics of neuropathic pain such as mechanical and thermal hypersensitivity. Spinal cord GT1b functions as an TLR2 agonist and induces proinflammatory microglia activation and central sensitization. Pharmacological inhibition of GT1b synthesis attenuates nerve injury-induced spinal cord microglia activation and pain hypersensitivity. Thus, the St3gal2-GT1b-TLR2 axis may offer a novel therapeutic target for the treatment of neuropathic pain.
Learn More >The trigeminal autonomic reflex is a physiologic reflex that plays a crucial role in primary headache and particularly in trigeminal autonomic cephalalgias, such as cluster headache. Previous studies have shown that this reflex can be modulated by the vagus nerve, leading to an inhibition of the parasympathetic output of the reflex in healthy participants. The aim of the present study was to characterize neural correlates of the modulatory effect of noninvasive vagus nerve stimulation (nVNS) on the trigeminal autonomic reflex.
Learn More >While much brain research on fibromyalgia (FM) focuses on the study of hyper-responsiveness to painful stimuli, some studies suggest that the increased pain-related brain activity often reported in FM studies may be in part explained by stronger responses to salient aspects of the stimulation rather than, or in addition to, its painfulness. We thus hypothesized that FM patients would demonstrate elevated brain responses to both pain onset and offset, two salient sensory events of opposing valences.
Learn More >A high-intensity potentially tissue-injuring stimulus generates a homotopic response to escape the stimulus and is associated with an affective phenotype considered to represent pain. In the face of tissue or nerve injury, the afferent encoding systems display robust changes in the input-output function, leading to an ongoing sensation reported as painful and sensitization of the nociceptors such that an enhanced pain state is reported for a given somatic or visceral stimulus. Our understanding of the mechanisms underlying this non-linear processing of nociceptive stimuli has led to our appreciation of the role played by the functional interactions of neural and immune signaling systems in pain phenotypes. In pathological states, neural systems interact with the immune system through the actions of a variety of soluble mediators, including cytokines. Cytokines are recognized as important mediators of inflammatory and neuropathic pain, supporting system sensitization and the development of a persistent pathologic pain. Cytokines can induce a facilitation of nociceptive processing at all levels of the neuraxis including supraspinal centers where nociceptive input evokes an affective component of the pain state. We review here several key proinflammatory and anti-inflammatory cytokines/chemokines and explore their underlying actions at four levels of neuronal organization: (1) peripheral nociceptor termini; (2) dorsal root ganglia; (3) spinal cord; and (4) supraspinal areas. Thus, current thinking suggests that cytokines by this action throughout the neuraxis play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury.
Learn More >To evaluate the efficacy of orvepitant (10 or 30 mg given once daily, orally for 4 weeks), a neurokinin-1 receptor antagonist, compared with placebo in reducing the intensity of epidermal growth factor receptor inhibitor (EGFRI)-induced intense pruritus.
Learn More >Assessing features of centralized pain may prove to be clinically meaningful in pediatric populations. However, we are currently limited by the lack of validated pediatric measures.
Learn More >Central poststroke pain (CPSP) is one of the neuropathic pain syndromes that can occur following stroke involving the somatosensory system. However, the underlying mechanism of CPSP remains largely unknown. Here, we established a CPSP mouse model by inducing a focal hemorrhage in the thalamic ventrobasal complex and confirmed the development of mechanical allodynia. In this model, microglial activation was observed in the somatosensory cortex, as well as in the injured thalamus. By using a CSF1 receptor inhibitor, we showed that microglial depletion effectively prevented allodynia development in our CPSP model. In the critical phase of allodynia development, c-fos-positive neurons increased in the somatosensory cortex, accompanied by ectopic axonal sprouting of the thalamocortical projection. Furthermore, microglial ablation attenuated both neuronal hyperactivity in the somatosensory cortex and circuit reorganization. These findings suggest that microglia play a crucial role in the development of CPSP pathophysiology by promoting sensory circuit reorganization.
Learn More >To report efficacy and safety of galcanezumab in adults with chronic cluster headache.
Learn More >The aim of this Delphi survey was to establish an international consensus on the most useful outcome measures for research on the effectiveness of non-pharmacological interventions for migraine. This is important, since guidelines for pharmacological trials recommend measuring the frequency of headaches with 50% reduction considered a clinically meaningful effect. It is unclear whether the same recommendations apply to complementary (or adjunct) non-pharmacological approaches, whether the same cut-off levels need to be considered for effectiveness when used as an adjunct or stand-alone intervention, and what is meaningful to patients.
Learn More >: Atopic dermatitis (AD) is a type of allergic/inflammatory dermatitis characterized by itch and an impairment in quality of life.: Herein, the authors review drug discovery efforts for AD, highlighting the clinical efficacy of novel drugs, with a particular focus on the relief of pruritus. Topical agents include emollients, topical antihistamines, corticosteroids, calcineurin inhibitors and herbs. Recently, topical phosphodiesterase E4 (PDE4) inhibitors like crisaborole have become available and are efficacious for mild to moderate AD with few side effects. For more severe AD, monoclonal antibodies like dupilumab are considered as efficacious subcutaneous treatment options. In severe and recalcitrant AD, systemic treatment can ameliorate AD symptoms.: Many topical and systemic medications have demonstrated therapeutic benefits for AD. Indeed, randomized trials have shown that topical PDE4 inhibitors and subcutaneous dupilumab are safe and efficacious. Objective tools to evaluate itch and gauge treatment efficacy is important, but current methodology relies primarily on clinical scores. AD is a systemic atopic disease with a lot of complicated psychosocial issues. Suboptimal efficacy is often due to poor compliance and unrealistic expectation of curative treatment, rendering treatment difficult despite the existence of effective medications.
Learn More >Chronic pain is a highly prevalent and complex health problem that is associated with a heavy symptom burden, substantial economic and social impact, and also, very few highly effective treatments. This review examines evidence for the efficacy and safety of magnesium in chronic pain. The previously published protocol for this review was registered in International Prospective Register of Systematic Reviews (PROSPERO), MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched until September 2018. We included randomized controlled trials (RCTs) comparing magnesium (at any dose, frequency, or route of administration) with placebo using participant-reported pain measures. A total of 9 RCTs containing 418 participants were included. Three studies examined neuropathic pain (62 participants), 3 examined migraines (190 participants), 2 examined complex regional pain syndrome (86 participants), and 1 examined low back pain with a neuropathic component (80 participants). Heterogeneity of included studies precluded any meta-analyses. No judgement could be made about safety because adverse events were inconsistently reported in the included studies. Evidence of analgesic efficacy from included studies was equivocal. However, reported efficacy signals in some of the included trials provide a rationale for more definitive studies. Future, larger-sized trials with good assay sensitivity and better safety assessment and reporting, as well as careful attention to formulations with optimal bioavailability, will serve to better define the role of magnesium in the management of chronic pain.
Learn More >To investigate plasma glucose changes during the ictal state of migraine compared to the interictal state.
Learn More >To evaluate the extent to which pain-related beliefs, appraisals, coping, and catastrophizing differ between countries, language groups, and country economy.
Learn More >The primary aim of this study was to better understand the role that social factors (i.e., social support, satisfaction in participation with social roles, social isolation, and self-perceived ability to perform social roles and activities) play in pain-related interference and depressive symptoms in adults with chronic pain. Moreover, this study also examined if sex exerts a moderating role in these associations.
Learn More >As one of the novel therapeutic drugs that targets Calcitonin gene-related peptide (CGRP), 75 mg rimegepant has been used for the acute management of migraine, which is one of the most common neurological diseases worldwide. Several clinical trials have been conducted to investigate the efficacy and safety of rimegepant for the acute management of migraine, but no systematic review of existing literature has been performed. We therefore performed a meta-analysis to investigate the efficacy and safety of rimegepant in treatment of patients with migraine.
Learn More >Neuropathic pain is a frequent condition caused by a lesion or disease of the central or peripheral somatosensory nervous system. A frequent cause of peripheral neuropathic pain is diabetic neuropathy. Its complex pathophysiology is not yet fully elucidated, which contributes to underassessment and undertreatment. A mechanism-based treatment of painful diabetic neuropathy is challenging but phenotype-based stratification might be a way to develop individualized therapeutic concepts. Our goal is to review current knowledge of the pathophysiology of peripheral neuropathic pain, particularly painful diabetic neuropathy. We discuss state-of-the-art clinical assessment, validity of diagnostic and screening tools, and recommendations for the management of diabetic neuropathic pain including approaches towards personalized pain management. We also propose a research agenda for translational research including patient stratification for clinical trials and improved preclinical models in relation to current knowledge of underlying mechanisms.
Learn More >Opioid drugs are the gold standard for the management of pain, but their use is severely limited by dangerous and unpleasant side effects. All clinically available opioid analgesics bind to and activate the mu-opioid receptor (MOR), a heterotrimeric G-protein-coupled receptor, to produce analgesia. The activity of these receptors is modulated by a family of intracellular RGS proteins or regulators of G-protein signaling proteins, characterized by the presence of a conserved RGS Homology (RH) domain. These proteins act as negative regulators of G-protein signaling by serving as GTPase accelerating proteins or GAPS to switch off signaling by both the Gα and βγ subunits of heterotrimeric G-proteins. Consequently, knockdown or knockout of RGS protein activity enhances signaling downstream of MOR. In this review we discuss current knowledge of how this activity, across the different families of RGS proteins, modulates MOR activity, as well as activity of other members of the opioid receptor family, and so pain and analgesia in animal models, with particular emphasis on RGS4 and RGS9 families. We discuss inhibition of RGS proteins with small molecule inhibitors that bind to sensitive cysteine moieties in the RH domain and the potential for targeting this family of intracellular proteins as adjuncts to provide an opioid sparing effect or as standalone analgesics by promoting the activity of endogenous opioid peptides. Overall, we conclude that RGS proteins may be a novel drug target to provide analgesia with reduced opioid-like side effects, but that much basic work is needed to define the roles for specific RGS proteins, particularly in chronic pain, as well as a need to develop newer inhibitors.
Learn More >Recent work, both clinical and experimental, suggests that the hypothalamic hormone oxytocin (OT) and its receptor (OTR) may be involved in migraine pathophysiology. In order to better understand possible central actions of OT in migraine/headache pathogenesis, we mapped the distribution of OT and OTR in nerve cells and fibers in rat brain with a focus on areas related to migraine attacks and/or shown previously to contain calcitonin gene related peptide (CGRP), another neuropeptide involved in migraine.
Learn More >Traumatic spinal cord injury (SCI) has devastating implications for patients, including a high predisposition for developing chronic pain distal to the site of injury. Chronic pain develops weeks to months after injury, consequently, patients are treated after irreparable changes have occurred. Nociceptors are central to chronic pain; however, the diversity of this cellular population presents challenges to understanding mechanisms and attributing pain modalities to specific cell types. To begin to address how peripheral sensory neurons below the injury level may contribute to the below-level pain reported by SCI patients, we examined SCI-induced changes in gene expression in lumbar dorsal root ganglia (DRG) below the site of injury. SCI was performed at the T10 vertebral level, with injury produced by a vessel clip with a closing pressure of 15 for 1 min. Alterations in gene expression produce long-term sensory changes, therefore, we were interested in studying SCI-induced transcripts before the onset of chronic pain, which may trigger changes in downstream signaling pathways and ultimately facilitate the transmission of pain. To examine changes in the nociceptor subpopulation in DRG distal to the site of injury, we retrograde labeled sensory neurons projecting to the hairy hindpaw skin with fluorescent dye and collected the corresponding lumbar (L2-L6) DRG 4 days post-injury. Following dissociation, labeled neurons were purified by fluorescence-activated cell sorting (FACS). RNA was extracted from sorted sensory neurons of naïve, sham, or SCI mice and sequenced. Transcript abundances validated that the desired population of nociceptors were isolated. Cross-comparisons to data sets from similar studies confirmed, we were able to isolate our cells of interest and identify a unique pattern of gene expression within a subpopulation of neurons projecting to the hairy hindpaw skin. Differential gene expression analysis showed high expression levels and significant transcript changes 4 days post-injury in SCI cell populations relevant to the onset of chronic pain. Regulatory interrelationships predicted by pathway analysis implicated changes within the synaptogenesis signaling pathway as well as networks related to inflammatory signaling mechanisms, suggesting a role for synaptic plasticity and a correlation with pro-inflammatory signaling in the transition from acute to chronic pain.
Learn More >Recent findings from rodent studies suggest that high-fat diet (HFD) increases hyperalgesia independent of obesity status. Furthermore, weight loss interventions such as voluntary physical activity (PA) for adults with obesity or overweight was reported to promote pain reduction in humans with chronic pain. However, regardless of obesity status, it is not known whether HFD intake and sedentary (SED) behavior is underlies chronic pain susceptibility. Moreover, differential gene expression in the nucleus accumbens (NAc) plays a crucial role in chronic pain susceptibility. Thus, the present study used an adapted model of the inflammatory prostaglandin E2 (PGE2)-induced persistent hyperalgesia short-term (PH-ST) protocol for mice, an HFD, and a voluntary PA paradigm to test these hypotheses. Therefore, we performed an analysis of differential gene expression using a transcriptome approach of the NAc. We also applied a gene ontology enrichment tools to identify biological processes associated with chronic pain susceptibility and to investigate the interaction between the factors studied: diet (standard diet vs. HFD), physical activity behavior (SED vs. PA) and PH-ST (PGE vs. saline). Our results demonstrated that HFD intake and sedentary behavior promoted chronic pain susceptibility, which in turn was prevented by voluntary physical activity, even when the animals were fed an HFD. The transcriptome of the NAc found 2,204 differential expression genes and gene ontology enrichment analysis revealed 41 biologic processes implicated in chronic pain susceptibility. Taking these biological processes together, our results suggest that genes related to metabolic and mitochondria stress were up-regulated in the chronic pain susceptibility group (SED-HFD-PGE), whereas genes related to neuroplasticity were up-regulated in the non-chronic pain susceptibility group (PA-HFD-PGE). These findings provide pieces of evidence that HFD intake and sedentary behavior provoked gene expression changes in the NAc related to promotion of chronic pain susceptibility, whereas voluntary physical activity provoked gene expression changes in the NAc related to prevention of chronic pain susceptibility. Finally, our findings confirmed previous literature supporting the crucial role of voluntary physical activity to prevent chronic pain and suggest that low levels of voluntary physical activity would be helpful and highly recommended as a complementary treatment for those with chronic pain.
Learn More >Movement representation techniques such as motor imagery (MI) and action observation (AO) could play an important role in the field of rehabilitation of patients with musculoskeletal pain; however, the effects of these tools on clinical pain remain unclear. Our objective is therefore to develop a systematic review and meta-analysis of the effects of MI and AO regarding pain intensity on patients with musculoskeletal pain. Databases and data treatment MEDLINE, EMBASE, CINAHL and Google Scholar were searched. Last search was run on July 2019. Meta-analysis was conducted to determine the effectiveness on pain intensity in patients with post-surgical pain or chronic pain, and GRADE was used to rate the quality, certainty, and applicability of the evidence.
Learn More >To characterize the clinical features of a large sample of children, adolescents, and young adults with a history of status migrainosus (SM) and to describe their short-term prognosis.
Learn More >The objective of this study was to develop and investigate the usability of a biofeedback treatment smartphone app for adolescent migraine sufferers.
Learn More >As a post-approval commitment, this dose-ranging study was undertaken to evaluate efficacy and safety of onabotulinumtoxinA in adolescents.
Learn More >Fibromyalgia is a syndrome characterized by generalized chronic musculoskeletal pain, hyperalgesia in specific points, and psychosomatic symptoms, such as fatigue, sleep disturbances (waking unrefreshed), anxiety, depression, cognitive dysfunction, headache, and gastrointestinal disorders. Investigations with non-pharmacological therapies, focused on physical therapy, have increased in recent years as alternative therapies for the treatment of fibromyalgia. The purpose of this review is to summarize the main physical therapy modalities used to treat fibromyalgia.
Learn More >To conduct a systematic literature review of spinal cord stimulation (SCS) for pain.
Learn More >To explore naturally occurring clinical subgroups of post-traumatic headache.
Learn More >Neuroimmune-glia interactions have been implicated in the development of neuropathic pain. Interleukin-27 (IL-27) is a cytokine that presents regulatory activity in inflammatory conditions of the central nervous system. Thus, we hypothesized that IL-27 would participate in the neuropathic pain process. Here, we found that neuropathic pain caused by peripheral nerve injury (spared nerve injury model; SNI), was enhanced in IL-27-deficient mice, whereas nociceptive pain is similar to that of wild-type mice. SNI induced an increase in the expression of IL-27 and its receptor subunit () in the sensory ganglia and spinal cord. IL-27 receptor was expressed mainly in resident macrophage, microglia, and astrocytes of the sensory ganglia and spinal cord, respectively. Finally, we identify that the antinociceptive effect of IL-27 was not observed in IL-10 mice. These results provided evidence that IL-27 is a cytokine produced after peripheral nerve injury that counteracts neuropathic pain development through induction of the antinociceptive cytokine IL-10. In summary, our study unraveled the role of IL-27 as a regulatory cytokine that counteracts the development of neuropathic pain after peripheral nerve damage. In conclusion, they indicate that immunotherapies based on IL-27 could emerge as possible therapeutic approaches for the prevention of neuropathic pain development after peripheral nerve injury.
Learn More >This chapter overviews research neuroimaging findings of patients with medication-overuse headache (MOH). Results indicate; (i) correlations between neuropathology and medication-overuse; (ii) changes in brain morphology and cortical function; and (iii) brain recovery subsequent to withdrawal of medication that was overused. Results of this narrative review indicate exacerbated brain structural and functional changes in regions of the pain-matrix and in regions of the mesocortical-limbic circuit in patients with MOH compared to patients with migraine or compared to healthy controls. Modification of brain morphology as well as an association between brain recovery and medication withdrawal suggest that the MOH disease process involves state (brain modification) and trait-like (brain adaptation and recovery) neuromechanisms.
Learn More >The individual and social burdens associated with chronic pain have been escalating globally. Accurate pain measurement facilitates early diagnosis, disease progression monitoring and therapeutic efficacy evaluation, thus is a key for the management of chronic pain. Although the "golden standards" of pain measurement are self-reported scales in clinical practice, the reliability of these subjective methods could be easily affected by patients' physiological and psychological status, as well as the assessors' predispositions. Therefore, objective pain assessment has attracted substantial attention recently. Previous studies of functional magnetic resonance imaging (fMRI) revealed that certain cortices and subcortical areas are commonly activated in subjects suffering from pain. Dynamic pain connectome analysis also found various alterations of neural network connectivity that are correlated with the severity of clinical pain symptoms. Electroencephalograph (EEG) demonstrated suppressed spontaneous oscillations during pain experience. Spectral power and coherence analysis of EEG also identified signatures of different types of chronic pain. Furthermore, fMRI and EEG can visualize objective brain activities modulated by analgesics in a mechanism-based way, thus bridge the gaps between animal studies and clinical trials. Using fMRI and EEG, researchers are able to predict therapeutic efficacy and identify personalized optimal first-line regimens. In the future, the emergence of magnetic resonance spectroscopy and cell labelling in MRI would encourage the investigation on metabolic and cellular pain biomarkers. The incorporation of machine learning algorithms with neuroimaging or behavior analysis could further enhance the specificity and accuracy of objective pain assessments.
Learn More >Acute pruritus occurs in various disorders. Despite severe repercussions on quality of life treatment options remain limited. Voltage-gated sodium channels (Na) are indispensable for transformation and propagation of sensory signals implicating them as drug targets. Here, Na1.7, 1.8 and 1.9 were compared for their contribution to itch by analysing Na-specific knockout mice. Acute pruritus was induced by a comprehensive panel of pruritogens (C48/80, endothelin, 5-HT, chloroquine, histamine, lysophosphatidic acid, trypsin, SLIGRL, β-alanine, BAM8-22), and scratching was assessed using a magnet-based recording technology. We report an unexpected stimulus-dependent diversity in Na channel-mediated itch signalling. Na1.7 showed substantial scratch reduction mainly towards strong pruritogens. Na1.8 impaired histamine and 5-HT-induced scratching while Na1.9 was involved in itch signalling towards 5-HT, C48/80 and SLIGRL. Furthermore, similar microfluorimetric calcium responses of sensory neurons and expression of itch-related TRP channels suggest no change in sensory transduction but in action potential transformation and conduction. The cumulative sum of scratching over all pruritogens confirmed a leading role of Na1.7 and indicated an overall contribution of Na1.9. Beside the proposed general role of Na1.7 and 1.9 in itch signalling, scrutiny of time courses suggested Na1.8 to sustain prolonged itching. Therefore, Na1.7 and 1.9 may represent targets in pruritus therapy.
Learn More >Chronic low back pain has both substantial social and economic impacts on patients and healthcare budgets. Adding to the magnitude of the problem is the difficulty in identifying the exact causes of disc degeneration with modern day diagnostic and imaging techniques. With that said, current non-operative and surgical treatment modalities for discogenic low back pain fails to meet the expectations in many patients and hence the challenge. The objective for newly emerging stem cell regenerative therapy is to treat degenerative disc disease (DDD) by restoring the disc's cellularity and modulating the inflammatory response. Appropriate patient selection is crucial for the success of stem cell therapy. Regenerative modalities for discogenic pain currently focus on the use of either primary cells harvested from the intervertebral discs or stem cells from other sources whether autogenic or allogenic. The microenvironment in which stem cells are being cultured has been recognized to play a crucial role in directing or maintaining the production of the desired phenotypes and may enhance their regenerative potential. This has led to a more specific focus on innovating more effective culturing techniques, delivery vehicles and scaffolds for stem cell application. Although stem cell therapy might offer an attractive alternative treatment option, more clinical studies are still needed to establish on the safety and feasibility of such therapy. In this literature review, we aim to present the most recent and studies related to the use of stem cell therapy in the treatment of discogenic low back pain.
Learn More >Health-related quality of life in chronic low back pain (LBP) is an important issue since various individual factors such as perceived loss of autonomy, inability to continue daily life and anxiety can contribute to maintenance or deterioration of this condition. Health-related quality of life is also important because it can predict the probability of recovery or recrudescence over time. In the literature, there is no systematic review on this topic. The present paper describes a protocol of the first systematic review and meta-analysis aimed at summarising the data on health-related quality of life in patients with chronic LBP compared with healthy controls. Gender, age and comorbidity of psychiatric disorders (mood or anxiety disorders) will be explored as moderators. Studies will be included if they used a case-control design comparing adults with chronic LBP to healthy controls on health-related quality of life through validated interviews/questionnaires.
Learn More >Osteoarthritis (OA) and pain are both made more severe by low-grade inflammation. We examined whether visceral fat, a major source of inflammatory cytokines and adipokines, was associated with an increased risk of knee OA or of musculoskeletal pain.
Learn More >In light of growing concerns about opioid analgesics, developing new non-pharmacologic pain control techniques has become a high priority. Adjunctive virtual reality can help reduce acute pain during painful medical procedures. However, for some especially painful medical procedures such as burn wound cleaning, clinical researchers recommend that more distracting versions of virtual reality are needed, to further amplify the potency of virtual reality analgesia. The current study with healthy volunteers explores for the first time whether interacting with virtual objects in Virtual Reality (VR) via "hands free" eye-tracking technology integrated into the VR helmet makes VR more effective/powerful than non-interactive/passive VR (no eye-tracking) for reducing pain during brief thermal pain stimuli.
Learn More >Previous studies suggested that both maladaptive stress response and circadian dysregulation might have a role in the background of migraine. However, effects of circadian genes on migraine have not been tested yet. In the present study, we investigated the main effect of rs10462028 of the circadian locomotor output cycles kaput () gene and its interaction with different stress factors on migraine. In our cross-sectional study 2,157 subjects recruited from Manchester and Budapest completed the ID-Migraine questionnaire to detect migraine type headaches (migraineID). Additional stress factors were assessed by a shortened version of the Childhood Trauma Questionnaire, the List of Threatening Experiences questionnaire, and a validated questionnaire to identify financial difficulties. Rs10462028 showed no main genetic effect on migraineID. However, chronic stress indexed by financial difficulties showed a significant interaction effect with rs10462028 ( = 0.006 in recessive model) on migraineID. This result remained significant after correction for lifetime bipolar and unipolar depression and was replicated in both subsamples, although only a trend effect was reached after Bonferroni-correction, which is the strictest correction not considering interdependences. Childhood adversity (CHA) and Recent negative life events (RLE) showed no significant gene × stress interaction with rs10462028. In addition, analysis demonstrated that the genetic region tagged by rs10462028 alters the binding of several miRNAs. Our exploratory study suggests that variations in the gene, with moderating effect on gene function through miRNA binding, in interaction with financial difficulties might influence the risk of migraine-type headaches. Thus, financial hardship as a chronic stress factor may affect migraine through altering circadian rhythms.
Learn More >Effective treatment of inflammatory pain is a major clinical concern for both patients and physicians. Traditional analgesics such as morphine and coxibs are not effective in all patients and have various unwanted side effects. Accumulating evidence has suggested that endomorphins (EMs), particularly EM-1, possess potent anti-inflammatory effects. However, poor bioavailability and low resistance to enzymatic degradation impede their direct application in the treatment of inflammation. A series of novel peptides based on the structure of EM-1, with lower undesired effects than their parent compounds, called MEL-EMs were discovered and synthetized in our preceding studies. Here, we selected two (MEL-0614 and MEL-N1606) to further investigate their anti-inflammatory effects. This work showed that MEL analogs exerted potent analgesic effects with the inhibition of activated glial cells and macrophages in a CFA-induced inflammatory pain model. Furthermore, multiple-dose administration of MEL analogs did not prolong CFA-induced chronic inflammatory pain, in contrast to morphine. Together, our findings revealed that MEL analogs may serve as effective candidates for chronic inflammation treatment.
Learn More >Microglia (MG) are the first cells to react to the abnormal incoming signals that follow an injury of sensory nerves and play a critical role in the development and maintenance of neuropathic pain, a common sequel of nerve injuries. Here we present population data on cell number, soma size, and length of processes of MG in the caudal division of the spinal trigeminal nucleus (Sp5C) in control mice and at the peak of microgliosis (7 days) following unilateral transection of the infraorbital nerve (IoN). The study is performed combining several bias- and assumption-free imaging and stereological approaches with different immunolabeling procedures, with the objective of tackling some hard problems that often hinder proper execution of MG morphometric studies. Our approach may easily be applied to low-density MG populations, but also works, with limited biases, in territories where MG cell bodies and processes form dense meshworks. In controls, and contralaterally to the deafferented side, MG cell body size and shape and branching pattern matched well the descriptions of "resting" or "surveillant" MG described elsewhere, with only moderate intersubject variability. On the superficial laminae of the deafferented side, however, MG displayed on average larger somata and remarkable diversity in shape. The number of cells and the length of MG processes per mm increased 5 and 2.5 times, respectively, indicating a net 50% decrease in the mean length of processes per cell. By using specific immunolabeling and cell sorting of vascular macrophages, we found only a negligible fraction of these cells in Sp5C, with no differences between controls and deafferented animals, suggesting that blood-borne monocytes play at most a very limited role in the microgliosis occurring following sensory nerve deafferentation. In sum, here we present reliable morphometric data on MG in control and deafferented trigeminal nuclei using efficient methods that we propose may equally be applied to any morphometric population analysis of these cells under different physiological or pathological conditions.
Learn More >The spinal N-methyl-D-aspartate (NMDA) receptor, and particularly its NR2B subunit, plays a pivotal role in neuropathic pain. However, the role of peripheral NMDA receptor in neuropathic pain is less well understood. We first treated cultured human keratinocytes, HaCaT cells with NMDA or NR2B-specific antagonist, ifenprodil and evaluated the level of total and phosphorylated NR2B at 24h using Western blot. Next, using the chronic post-ischemia pain (CPIP) model, we administered NMDA or ifenprodil subcutaneously into the hind paws of male rats. Nociceptive behaviors were assessed by measuring mechanical and thermal withdrawal thresholds. Expression and phosphorylation of NR2B on keratinocyte were analyzed at 6, 12, 18, and 24 h on day 1 (initiation of pain) as well as day 2, 6, 10 and 14 (development and maintenance of pain) after the ischemia. The level of peripheral sensitization-related proteins (nuclear factor-κB (NF-κB), extracellular regulated protein kinases (ERK), and interleukin-1β (IL-1β)) in epidermis and dorsal root ganglion (DRG) were evaluated by immunofluorescence and western blot. Central sensitization-related C-fos induction, as well as astrocytes and microglia activation in the spinal cord dorsal horn (SDH) were studied using immunofluorescence. Administration of NMDA upregulated NR2B phosphorylation on HaCaT cells. CPIP-induced mechanical allodynia and thermal hyperalgesia were intensified by NMDA and alleviated by ifenprodil. CPIP resulted in an early upregulation of NR2B (peaked at 24h) and late phosphorylation of NR2B (peaked at 14d) in hindpaw keratinocytes. CPIP led to an upregulation and phosphorylation of NF-κB and ERK, as well as an increased IL-1β production in the ipsilateral skin and DRG. CPIP-associated c-fos induction in SDH persisted from acute to chronic stages after ischemia, while microglia and astrocyte activation were only observed in chronic phase. These CPIP-induced changes were also suppressed by ifenprodil administered subcutaneously in the hind paw. Our findings reveal a previously unrecognized role of keratinocyte NMDA receptor subunit 2B in peripheral and central nociceptive sensitization induced by CPIP.
Learn More >Recurrent and intractable chronic itch is a world-wide problem but mechanisms, especially the neural mechanisms, underlying chronic itch still remain unclear. In this study, we investigated the peripheral and spinal mechanisms responsible for prolonged itch in a mouse model of allergic contact dermatitis (ACD) induced by squaric acid dibutylester (SADBE). We found that repeated exposure of mice to SADBE evoked persistent spontaneous scratching and significantly aberrant cutaneous and systemic immune responses lasting for weeks. SADBE induced itch requires both nonhistaminergic and histaminergic pathways, which are likely relayed by gastrin-releasing peptide receptor (GRPR) and natriuretic peptide receptor A (NPRA) in the spinal cord respectively. Employing genetic, pharmacology, RNAscope assay and cell-specific ablation methods, we dissected a neural circuit for the prolonged itch formed as Grpr neurons act downstream of Npr1 neurons in the spinal cord. Taken together, our data suggested that targeting GRPR and NPRA may provide effective treatments for ACD associated chronic pruritus.
Learn More >Previously, we showed internal low intensity focused ultrasound (liFUS) improves nociceptive thresholds in rats with vincristine-induced neuropathy (VIN) for 48-h post-treatment. Here, we perform more rigorous behavioral testing with the internal device and introduce external liFUS treatment. Behavioral testing confirmed VIN induced neuropathy (Von Frey fibers, VFF; hot plate, HPT; locomotion, OFT). This was followed by internal or external liFUS treatment (2.5 W or 8 W, for 3 min, respectively) to the left L5 dorsal root ganglia (DRG). A thermocouple placed at the DRG documented temperature changes during treatment, to confirm the modulatory nature of our treatment. Behavioral testing was performed pre-liFUS, and for five consecutive days post-liFUS. Groups included: (1) VIN/liFUS, (2) saline/liFUS, (3) VIN/sham liFUS, and (4) saline/sham liFUS. Significant improvements in mechanical (VFF) and thermal (HPT) nociceptive thresholds were seen in the VIN/liFUS group following both internal and external treatment. Hematoxylin and Eosin, and Fluorojade staining showed no histological damage to the DRG. Internal liFUS treatment produced a mean temperature rise of 3.21 ± 0.30 °C, whereas external liFUS resulted in a mean temperature rise of 1.78 °C ± 0.21 °C. We demonstrate that, in a VIN rat model, external liFUS treatment of the L5 DRG significantly reduces nociceptive sensitivity thresholds without causing tissue damage.
Learn More >We surveyed the American Headache Society (AHS) New Investigators and Trainees Section (NITS), and International Headache Academy (IHA) attendees to better understand what they perceive as the most pressing issues for themselves as new investigators and trainees in the field of headache medicine.
Learn More >Almost one-quarter of Asian patients with diabetes experience diabetic peripheral neuropathic pain (DPNP), which may be associated with moderate or severe levels of pain, insomnia, mood disorders, and worsened quality of life. Current treatments are generally ineffective and may be poorly tolerated. We evaluated mirogabalin as a treatment for DPNP in Asian subjects.
Learn More >Musculoskeletal (MSK) pain is the primary contributor to disability worldwide. There is a growing consensus that MSK pain is a recurrent multifactorial condition underpinned by health and lifestyle factors. Studies suggest that education on work-related pain and individualised advice could be essential and effective for managing persistent MSK pain.
Learn More >Psychological characteristics are important in the development and progression of low back pain (LBP), however their role in persistent, severe LBP is unclear.
Learn More >Occurrence, risk factors, and impact on daily life of chronic pain after critical illness have not been systematically studied.
Learn More >Pain and emotional distress have a reciprocal relation. The amygdala has been implicated in emotional processing. The central nucleus of amygdala (CeA) receives nociceptive information from the dorsal horn of spinal cord, and responsible for the central plasticity in chronic pain. Neuropathic pain is a type of severe chronic pain and can be strongly influenced by emotional components. Plastic changes in CeA may play a key role in the development and/or maintenance of neuropathic pain. We studied the expression levels of proteins in CeA of spinal nerve transection (SNT) model rats. Total tissue lysate proteins were separated by two dimensional-gel electrophoresis (2D-PAGE). Gels from different time points were compared using Progenesis SameSpot software, and the spots with Fold Change greater than 2 were excised for the protein identification by mass spectrometry. We identified more than 50 cytosolic proteins as significantly altered in their expressions in CeA of SNT rats, and most of these changes have been validated at mRNA levels by qRT-PCR. We also identified more than 40 membrane proteins as notably up- or down-regulated in CeA of SNT model rats relative to a control using stable isotope dimethyl labeling nano-LC-MS/MS based proteomics and found that one of such protein, doublecortin, is specifically localized in the membrane fraction without changes in total amount of the protein. Immunohistochemistry showed that doublecortin is expressed in processes in CeA of rats 7 and 21 days post SNT surgery, suggesting doublecorin is one of the proteins which may contribute to the plastic changes in CeA in the neuropathic pain model. These dysregulated proteins may play roles in reciprocal relationships between pain and psychological distress in the amygdala and contribute to central sensitization.
Learn More >To evaluate measurement and associations between pain severity and opioid craving in individuals with chronic pain on long-term opioid therapy and/or with opioid use disorder.
Learn More >Chronic neuropathic pain associated with peripheral neuropathies cannot be attributed solely to lesions of peripheral sensory axons and likely involves alteration in the processing of nociceptive information in the central nervous system in most patients. Few data are available regarding EEG correlates of chronic neuropathic pain. The fact is that effective cortical neuromodulation strategies to treat neuropathic pain target the precentral cortical region, i.e. a cortical area corresponding to the motor cortex. It is not known how these strategies might modulate brain rhythms in the central cortical region, but it can be speculated that sensorimotor rhythms (SMRs) are modified. Another potent way of modulating cortical rhythms is to use EEG-based neurofeedback (NFB). Rare studies previously aimed at relieving neuropathic pain using EEG-NFB training.
Learn More >Stratified care involves subgrouping patients based on key characteristics, e.g. prognostic risk, and matching these subgroups to appropriate early treatment options. The STarT MSK feasibility and pilot cluster randomised controlled trial (RCT) examined the feasibility of a future main trial and of delivering prognostic stratified primary care for patients with musculoskeletal pain. The pilot RCT was conducted in 8 UK general practices (4 stratified care; 4 usual care) with 524 patients. GPs in stratified care practices were asked to use i) the Keele STarT MSK development tool for risk-stratification and ii) matched treatment options for patients at low-, medium- and high-risk of persistent pain. This paper reports on a nested qualitative study exploring the feasibility of delivering stratified care ahead of the main trial.
Learn More >Musculoskeletal (MSK) pain from the five most common presentations to primary care (back, neck, shoulder, knee or multi-site pain), where the majority of patients are managed, is a costly global health challenge. At present, first-line decision-making is based on clinical reasoning and stratified models of care have only been tested in patients with low back pain. We therefore, examined the feasibility of; a) a future definitive cluster randomised controlled trial (RCT), and b) General Practitioners (GPs) providing stratified care at the point-of-consultation for these five most common MSK pain presentations.
Learn More >There exists a limited number of studies investigating the correlation between spinal adenosine A1 receptors and Vincristine-induced peripheral neuropathy (VIPN). This study explored the role of intrathecal N6-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA) in neuropathic pain induced in rats by administering vincristine (100 μg/kg i.p.) for 10 days (two 5-day cycles with a 2-day pause).
Learn More >The neuropeptide S/neuropeptide S receptor (NPS/NPSR) system is involved in the regulation of anxiety in rodents. Chronic inflammation can induce anxiety. Our lab has observed that electroacupuncture (EA) has a beneficial effect on chronic inflammatory pain and pain-related anxiety; however, the mechanism should be further clarified. In the present study, we used an inflammatory pain model to investigate the role of the NPS/NPSR system in the anterior cingulate cortex (ACC) in the analgesic and antianxiety effects of EA.
Learn More >Monocyte derived macrophages (MDMs) infiltrate sites of infection or injury and upregulate cyclooxygenase-2 (COX-2), an enzyme that stimulates prostaglandin-E2 (PgE2). Nanotheranostics combine therapeutic and diagnostic agents into a single nanosystem. In previous studies, we demonstrated that a nanotheranostic strategy, based on theranostic nanoemulsions (NE) loaded with a COX-2 inhibitor (celecoxib, CXB) and equipped with near-infrared fluorescent (NIRF) reporters, can specifically target circulating monocytes and MDMs. The anti-inflammatory and anti-nociceptive effects of such cell-specific COX-2 inhibition lasted several days following Complete Freund's Adjuvant (CFA) or nerve injury in male mice. The overall goal of this study was to investigate the extended (up to 40 days) impact of MDM-targeted COX-2 inhibition and any sex-based differences in treatment response; both of which remain unknown. Our study also evaluates the feasibility and efficacy of a preclinical nanotheranostic strategy for mechanistic investigation of the impact of such sex differences on clinical outcomes. : CFA was administered into the right hind paws of male and female mice. All mice received a single intravenous dose of NIRF labeled CXB loaded NE twelve hours prior to CFA injection. whole body NIRF imaging and mechanical hypersensitivity assays were performed sequentially and NIRF imaging and immunohistopathology of foot pad tissues were performed at the end point of 40 days. : Targeted COX-2 inhibition of MDMs in male and female mice successfully improved mechanical hypersensitivity after CFA injury. However, we observed distinct sex-specific differences in the intensity or longevity of the nociceptive responses. In males, a single dose of CXB-NE administered via tail vein injection produced significant improved mechanical hypersensitivity for 32 days as compared to the drug free NE (DF-NE) (untreated) control group. In females, CXB-NE produced similar, though less prominent and shorter-lived effects, lasting up to 11 days. NIRF imaging confirmed that CXB-NE can be detected up to day 40 in the CFA injected foot pad tissues of both sexes. There were distinct signal distribution trends between males and females, suggesting differences in macrophage infiltration dynamics between the sexes. This may also relate to differences in macrophage turnover rate between the sexes, a possibility that requires further investigation in this model. : For the first time, this study provides unique insight into MDM dynamics and the early as well as longer-term targeted effects and efficacy of a clinically translatable nanotheranostic agent on MDM mediated inflammation. Our data supports the potential of nanotheranostics as presented in elucidating the kinetics, dynamics and sex-based differences in the adaptive or innate immune responses to inflammatory triggers. Taken together, our study findings lead us closer to true personalized, sex-specific pain nanomedicine for a wide range of inflammatory diseases.
Learn More >There is a high prevalence of painful diabetic polyneuropathy (pDPN) with around one-third of all patients with diabetes suffering from pDPN. pDPN has debilitating consequences, with a major impact on morbidity and quality of life. Unfortunately, there is no globally licenced pharmacotherapy that modulates the underlying disease mechanisms to prevent or halt the progression of diabetic neuropathy. The cornerstone of treatment therefore remains optimising glycaemic control and cardiovascular risk factors, and symptom control. Evidence from placebo-controlled studies has shown that antidepressants and anticonvulsants are effective for alleviating pDPN. Current clinical guidelines recommend the treatment of pDPN through the use of amitriptyline (tricyclic antidepressant), duloxetine (serotonin norepinephrine reuptake inhibitor), gabapentin and pregabalin (α2-δ ligands), tramadol and tapentadol (μ receptor agonists and norepinephrine reuptake inhibitors) and topical agents such as capsaicin (transient receptor potential V1 receptor desensitizer), although the latter is known to cause degeneration of small nerve fibers. pDPN can be difficult to treat, which frustrates healthcare providers, patients and caregivers. There is an additional need for clinical trials of novel therapeutic agents and optimal combinations for the management of pDPN. This article reviews the pharmacological management of pDPN, emerging therapies, the difficulties of placebo response in clinical trials and novel proposed biomarkers of treatment response.
Learn More >Repetitive transcranial magnetic stimulation (rTMS) is one of the effective treatments for neuropathic pain. Little is known about the effects of multi-session theta burst stimulation, one of the new paradigms of rTMS.
Learn More >Joint pain is a distressing symptom of arthritis, and it is frequently persistent even after treatments which reduce local inflammation. Continuous production of algogenic factors activate/sensitize nociceptors in the joint structures and contribute to persistent pain, a challenging and difficult condition to treat. TNF is a crucial cytokine for the pathogenesis of several rheumatic diseases, and its inhibition is a mainstay of treatment to control joint symptoms, including pain. Here, we sought to investigate the inflammatory changes and the role of TNF in dorsal root ganglia (DRG) during persistent hypernociception after the resolution of acute joint inflammation. Using a model of antigen-induced arthritis, the peak of joint inflammation occurred 12-24 h after local antigen injection and was characterized by an intense influx of neutrophils, pro-inflammatory cytokine production, and joint damage. We found that inflammatory parameters in the joint returned to basal levels between 6 and 8 days after antigen-challenge, characterizing the resolving phase of joint inflammation. Mechanical hyperalgesia was persistent up to 14 days after joint insult. The persistent nociception was associated with the inflammatory status of DRG after cessation of acute joint inflammation. The late state of neuroinflammation in the ipsilateral side was evidenced by gene expression of TNF, TNFR2, IL-6, IL-1β, CXCL2, COX2, and iNOS in lumbar DRG (L3-L5) and leukocyte adhesion in the lumbar intumescent vessels between days 6 and 8. Moreover, there were signs of resident macrophage activation in DRG, as evidenced by an increase in Iba1-positive cells. Intrathecal or systemic injection of etanercept, an agent clinically utilized for TNF neutralization, at day 7 post arthritis induction, alleviated the persistent joint hyperalgesia by specific action in DRG. Our data suggest that neuroinflammation in DRG after the resolution of acute joint inflammation drives continuous neural sensitization resulting in persistent joint nociception in a TNF-dependent mechanism.
Learn More >Endometriosis is a complex, heterogeneous, chronic inflammatory condition impacting ~176 million women worldwide. It is associated with chronic pelvic pain, infertility, and fatigue, and has a substantial impact on health-related quality of life. Endometriosis is defined by the growth of endometrial-like tissue outside the uterus, typically on the lining of the pelvic cavity and ovaries (known as "lesions"). Macrophages are complex cells at the center of this enigmatic condition; they are critical for the growth, development, vascularization, and innervation of lesions as well as generation of pain symptoms. In health, tissue-resident macrophages are seeded during early embryonic life are vital for development and homeostasis of tissues. In the adult, under inflammatory challenge, monocytes are recruited from the blood and differentiate into macrophages in tissues where they fulfill functions, such as fighting infection and repairing wounds. The interplay between tissue-resident and recruited macrophages is now at the forefront of macrophage research due to their differential roles in inflammatory disorders. In some cancers, tumor-associated macrophages (TAMs) are comprised of tissue-resident macrophages and recruited inflammatory monocytes that differentiate into macrophages within the tumor. These macrophages of different origins play differential roles in disease progression. Herein, we review the complexities of macrophage dynamics in health and disease and explore the paradigm that under disease-modified conditions, macrophages that normally maintain homeostasis become modified such that they promote disease. We also interrogate the evidence to support the existence of multiple phenotypic populations and origins of macrophages in endometriosis and how this could be exploited for therapy.
Learn More >Pain has a significant impact on the quality of life of patients with multiple sclerosis (MS). However, the neurophysiological mechanisms of central neuropathic pain in a MS course are not known. We hypothesized that changes in power spectral density (PSD) that take place in the electroencephalography (EEG) of MS patients with and without the central neuropathic pain (CNP) would differ. The study aimed to assess the features of quantitative EEG using the PSD indicator along with peak frequencies in the standard frequency bands in MS patients with and without CNP. We have analyzed the quantitative spectral content of the EEG at a resting state in 12 MS patients with CNP, 12 MS patients without CNP, and 12 gender- and age-matched healthy controls using fast Fourier transformation. Based on the ANOVA, at the group level, the theta band absolute and relative PSD showed an increase, whereas alpha band relative PSD showed a decrease in MS patients both with and without CNP. However, only in MS with CNP group, the absolute and relative PSD in the beta1 and beta2 bands increased and exceeded that in patients without pain. Only MS patients with CNP demonstrated the significantly increased absolute PSD for the theta, beta1, and beta2 frequency bands in most regions of interest. In the theta band, MS patients with CNP displayed the increase in absolute spectral power for the mid-temporal derivation of the right hemisphere and the increase in relative spectral power for the prefrontal derivation of this hemisphere. In the beta1 band, the increase in absolute spectral power was observed for the three temporal derivations of the right hemisphere, whereas in the beta2 band, for the occipital, parietal, and temporal lobes of both hemispheres. In the alpha band, only a relative spectral power decrease was revealed for the occipital lobes of both hemispheres and parietal lobe of the right hemisphere. In MS patients with CNP, the frequencies of the dominant spectral power (peak frequencies) in the high-frequency beta band were higher than in the healthy control in posterior areas of the left hemisphere. Data could represent central nervous system alterations related to central neuropathic pain in MS patients that lead to the disturbances in cortical communication.
Learn More >Gangliosides are abundantly occurring sialylated glycosphingolipids serving diverse functions in the nervous system. Membrane-localized gangliosides are important components of lipid microdomains (rafts) which determine the distribution of and the interaction among specific membrane proteins. Different classes of gangliosides are expressed in nociceptive primary sensory neurons involved in the transmission of nerve impulses evoked by noxious mechanical, thermal, and chemical stimuli. Gangliosides, in particular GM1, have been shown to participate in the regulation of the function of ion channels, such as transient receptor potential vanilloid type 1 (TRPV1), a molecular integrator of noxious stimuli of distinct nature. Gangliosides may influence nociceptive functions through their association with lipid rafts participating in the organization of functional assemblies of specific nociceptive ion channels with neurotrophins, membrane receptors, and intracellular signaling pathways. Genetic and experimentally induced alterations in the expression and/or metabolism of distinct ganglioside species are involved in pathologies associated with nerve injuries, neuropathic, and inflammatory pain in both men and animals. Genetic and/or pharmacological manipulation of neuronal ganglioside expression, metabolism, and action may offer a novel approach to understanding and management of pain.
Learn More >Haemophilic arthropathy is associated with pain that often becomes chronic, likely caused by peripheral and central mechanisms. In the field of haemophilia, to our knowledge, the role of the descending pain pathway, which can also be involved in these pain processes, has not been examined to date.
Learn More >Invasive motor cortex stimulation (iMCS) has been proposed as a treatment for intractable neuropathic pain syndromes. Although the mechanisms underlying the analgesic effect of iMCS remain largely elusive, several studies found iMCS-related changes in regional cerebral blood flow (rCBF) in neuropathic pain patients. The aim of this study was to meta-analyze the findings of neuroimaging studies on rCBF changes to iMCS.
Learn More >The main aim of this work was to identify and to share the lessons learned from the negative outcome of the mirogabalin ALDAY phase 3 clinical program in pain associated with fibromyalgia. These lessons are important to improve planning and design of future phase 3 programs in fibromyalgia. A systematic review from Cochrane Library, Medline, Embase, clinicaltrials.gov, pharmaceutical companies and regulatory agencies' websites, was carried out starting from the development of gabapentin, the first α2δ ligand studied for the treatment of neuropathic pain and ending with the mirogabalin program. Based on the outcome of the main fibromyalgia programs, several differences in design, primary endpoint choice, magnitude of placebo response, presence of an active comparator, and size of the entire clinical program were identified. This analysis focused on the negative primary results of the mirogabalin ALDAY program and identified several contributing factors. Above all, the magnitude of placebo response and the unprecedented size of the program were identified. The number of study visits and procedures was also high and highly demanding for all subjects involved in ALDAY. In terms of main lessons learned from ALDAY, the first was the need for a comprehensive patient-focused strategy to preliminarily identify the challenges of fibromyalgia based on patient perspective and study complexity. Second, there was a need for a harmonized, truly patient-centric, global regulatory guidance accepted by regulatory agencies. Third, ALDAY proved that a phase 2 proof of concept, dose ranging study is necessary before commencing any phase 3 program in fibromyalgia.
Learn More >Sleep quality and chronic neck pain (NP) are associated. However, the genetic influences on this association have not been explored. This study investigated the genetic and environmental influences on the association between sleep quality and chronic NP.
Learn More >Disturbances in the function of the mesostriatal dopamine system may contribute to the development and maintenance of chronic pain, including its sensory and emotional/cognitive aspects. In the present study, we assessed the influence of chronic constriction injury (CCI) of the sciatic nerve on the expression of genes coding for dopamine and opioid receptors as well as opioid propeptides in the mouse mesostriatal system, particularly in the nucleus accumbens. We demonstrated bilateral increases in mRNA levels of the dopamine D1 and D2 receptors (the latter accompanied by elevated protein level), opioid propeptides proenkephalin and prodynorphin, as well as delta and kappa (but not mu) opioid receptors in the nucleus accumbens at 7 to 14 days after CCI. These results show that CCI-induced neuropathic pain is accompanied by a major transcriptional dysregulation of molecules involved in dopaminergic and opioidergic signaling in the striatum/nucleus accumbens. Possible functional consequences of these changes include opposite effects of upregulated enkephalin/delta opioid receptor signaling vs. dynorphin/kappa opioid receptor signaling, with the former most likely having an analgesic effect and the latter exacerbating pain and contributing to pain-related negative emotional states.
Learn More >Cluster headache (CH), a severe primary headache, is often misdiagnosed and mismanaged. The aim of this study was to develop and evaluate a screening tool to aid the diagnosis of CH. We developed a novel 12-item screening tool. This was comprised of four components: (1) images depicting headache pain; (2) pain descriptors; (3) key questions that could differentiate between CH and migraine; and (4) a visual analogue pain scale. The total possible questionnaire score ranged from 3-32. Patients with CH and migraines (control group) were recruited prospectively from a headache centre in the North of England, UK. Two-hundred and ninety-six patients were included in the study: 81 CH patients, 36 of which suffer with episodic CH and 45 with chronic CH; 215 migraine patients, 92 of which suffer with episodic migraine and 123 with chronic migraine. The mean questionnaire score was higher in CH patients versus migraine patients (28.4 versus 19.5). At a cut-off score of >25 out of 32, the screening tool had a sensitivity of 86.4% and a specificity of 92.0% in differentiating between CH and migraine. The screening tool could be a useful instrument to aid the diagnosis of a CH. The images depicting headache pain do not clearly discriminate between CH and migraine.
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