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Single-cell RNA-sequencing and in vivo functional imaging provide expansive but disconnected views of neuronal diversity. Here, we developed a strategy for linking these modes of classification to explore molecular and cellular mechanisms responsible for detecting and encoding touch. By broadly mapping function to neuronal class, we uncovered a clear transcriptomic logic responsible for the sensitivity and selectivity of mammalian mechanosensory neurons. Notably, cell types with divergent gene-expression profiles often shared very similar properties, but we also discovered transcriptomically related neurons with specialized and divergent functions. Applying our approach to knockout mice revealed that Piezo2 differentially tunes all types of mechanosensory neurons with marked cell-class dependence. Together, our data demonstrate how mechanical stimuli recruit characteristic ensembles of transcriptomically defined neurons, providing rules to help explain the discriminatory power of touch. We anticipate a similar approach could expose fundamental principles governing representation of information throughout the nervous system.
Learn More >To examine the effect of sex on clinical response to triptans and to determine whether these differences are related to pharmacokinetics of triptans in men and women, we performed a systematic review and meta-analysis.
Learn More >Clinical μ-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have established an model of opioid-induced hyperalgesic priming (OIHP), in male rats, to identify nociceptor populations involved and its maintenance mechanisms. OIHP was induced by systemic administration of fentanyl and confirmed by prolongation of prostaglandin E (PGE) hyperalgesia. Intrathecal cordycepin, which reverses Type I priming, or the combination of Src and MAP kinase (MAPK) inhibitors, which reverses Type II priming, both partially attenuated OIHP. Parallel experiments were performed on small-diameter (<30 µm) dorsal root ganglion (DRG) neurons, cultured from fentanyl-primed rats, and rats with OIHP treated with agents that reverse Type I or Type II priming. Enhancement of the sensitizing effect of a low concentration of PGE (10 nm), another characteristic feature of priming, measured as reduction in action potential (AP) rheobase, was found in weakly isolectin B4 (IB4)-positive and IB4-negative (IB4-) neurons. In strongly IB4-positive (IB4+) neurons, only the response to a higher concentration of PGE (100 nm) was enhanced. The sensitizing effect of 10 nm PGE was attenuated in weakly IB4+ and IB4- neurons cultured from rats whose OIHP was reversed Thus, administration of fentanyl induces neuroplasticity in weakly IB4+ and IB4- nociceptors that persists and has properties of Type I and Type II priming. The mechanism underlying the enhanced sensitizing effect of 100 nm PGE in strongly IB4+ nociceptors, not attenuated by inhibitors of Type I and Type II priming, remains to be elucidated.Commonly used clinical opioid analgesics, such as fentanyl and morphine, can produce hyperalgesia and chronification of pain. To uncover the nociceptor population mediating opioid-induced hyperalgesic priming (OIHP), a model of pain chronification, and elucidate its underlying mechanism, at the cellular level, we established an model of OIHP. In dorsal root ganglion (DRG) neurons cultured from rats primed with fentanyl, robust nociceptor population-specific changes in sensitization by prostaglandin E (PGE) were observed, when compared with nociceptors from opioid naive rats. In DRG neurons cultured from rats with OIHP, enhanced PGE-induced sensitization was observed , with differences identified in non-peptidergic [strongly isolectin B4 (IB4)-positive] and peptidergic [weakly IB4-positive (IB4+) and IB4-negative (IB4-)] nociceptors.
Learn More >OnabotulinumtoxinA and agents that block calcitonin gene‒receptor peptide action have both been found to have anti-migraine effects, but they inhibit different populations of meningeal nociceptors. We therefore tested the effects of combined treatment with onabotulinumtoxinA and the calcitonin gene‒receptor peptide antagonist atogepant on activation/sensitization of trigeminovascular neurons by cortical spreading depression.
Learn More >Migraine attacks are often triggered by normally innocuous stimuli, suggesting that sensitization within the nervous system is present. One mechanism that may contribute to neuronal sensitization in this context is translation regulation of new protein synthesis. The goal of this study was to determine whether protein synthesis contributes to behavioral responses and priming in preclinical models of migraine.
Learn More >Peripheral denervation and pain are hallmarks of small fiber neuropathy (SFN). We investigated the contribution of skin cells on nociceptor degeneration and sensitization. We recruited 56 patients with SFN and 31 healthy controls, and collected skin punch biopsies for immunohistochemical and immunocytochemical analysis of netrin-1 (NTN1) and pro- and anti-inflammatory cytokine expression patterns. We further applied co-culture systems with murine dorsal root ganglion (DRG) neurons for skin cell-nerve interaction studies and patch-clamp analysis. Human keratinocytes attract murine DRG neuron neurites and the gene expression of the axon guidance cue NTN1 is higher in keratinocytes of SFN patients than in controls. NTN1 slows and reduces murine sensory neurite outgrowth in vitro, but does not alter keratinocyte cytokine expression. In the naïve state, keratinocytes of SFN patients show a higher expression of transforming growth factor-β1 (p<0.05), while fibroblasts display higher expression of the algesic cytokines interleukin (IL)-6 (p<0.01) and IL-8 (p<0.05). IL-6 incubation of murine DRG neurons leads to an increase in action potential firing rates compared to baseline (p<0.01). Our data provide evidence for a differential effect of keratinocytes and fibroblasts on nociceptor degeneration and sensitization in SFN compared to healthy controls and further supports the concept of cutaneous nociception.
Learn More >Chronic pain is highly prevalent in multiple sclerosis (MS). Pain heterogeneity may contribute to poor treatment outcomes. The aim of this study was to characterize pain phenotypes distributions in persons with multiple sclerosis (MS), and compare pain phenotypes in terms of pain intensity, frequency of chronic overlapping pain conditions, and use and analgesic effects of different classes of pain medications. Data were collected via a national web-based survey with measures of neuropathic (painDETECT) and nociplastic pain (Fibromyalgia survey criteria), chronic overlapping pain conditions, and pain medication use and pain relief. In a sample of N=842 adults with chronic pain and MS, the largest proportion (41%) showed evidence of nociceptive pain, 27% had mixed neuropathic/nociplastic pain, 23% had nociplastic pain, and 9% had neuropathic pain. Nociplastic pain was associated with significantly higher pain intensity and frequency of chronic overlapping pain conditions. Across all pain types, high frequency of pain medication use along with poor-modest pain relief were reported. Cannabis use for pain was more common and pain relief ratings were higher among those with nociplastic pain, relative to nociceptive pain. Although NSAIDs use was highest among those with nociplastic pain (80%), pain relief ratings for NSAIDs were highest among those with nociceptive pain. These findings underscore the need for multidimensional assessment of pain in MS with greater emphasis on the identification of pain phenotype. An improved characterization of pain as a multifaceted condition in MS could inform therapeutic approaches.
Learn More >Map the current literature investigating autonomy development, identity development, and peer relationships in young people aged 10-24 years with chronic pain.
Learn More >To examine the effect of sex on migraine trigger factors.
Learn More >Osteoarthritis (OA) manifests with chronic pain, motor impairment, and proprioceptive changes. However, the role of the brain in the disease is largely unknown. Here, we studied brain networks using the mathematical properties of graphs in a large sample of knee and hip OA (KOA, n = 91; HOA, n = 23) patients. We used a robust validation strategy by subdividing the KOA data into discovery and testing groups and tested the generalizability of our findings in HOA. Despite brain global topological properties being conserved in OA, we show there is a network wide pattern of reorganization that can be captured at the subject-level by a single measure, the hub disruption index. We localized reorganization patterns and uncovered a shift in the hierarchy of network hubs in OA: primary sensory and motor regions and parahippocampal gyrus behave as hubs and insular cortex loses its central placement. At an intermediate level of network structure, frontoparietal and cingulo-opercular modules showed preferential reorganization. We examined the association between network properties and clinical correlates: global disruption indices and isolated degree properties did not reflect clinical parameters; however, by modeling whole brain nodal degree properties, we identified a distributed set of regions that reliably predicted pain intensity in KOA and generalized to hip OA. Together, our findings reveal that while conserving global topological properties, brain network architecture reorganizes in OA, at both global and local scale. Network connectivity related to OA pain intensity is dissociated from the major hub disruptions, challenging the extent of dependence of OA pain on nociceptive signaling.
Learn More >In 2006, humans with a congenital insensitivity to pain (CIP) were found to lack functional Na 1.7 channels. In the 15 years since there has been a rush to develop selective Na 1.7 inhibitors with the goal of producing broadly effective analgesics without the problems of addiction and tolerance associated with opioids. Pharmacologically, this mission has been highly successful, leading to a number of highly potent and selective inhibitors of Na 1.7.However,there are very few examples where these inhibitors have yielded effective analgesia in preclinical pain models or human clinical trials. In this review we summarisethe role of Na 1.7 in nociception, its history as a therapeutic target, and the quest to develop potent inhibitors of this channel. Finally, we discuss possible reasons why the pain-free state seen in humans with CIP has been so elusive to recapitulate pharmacologically.
Learn More >Obesity is a global concern and affects millions of Americans who consume poor-quality diets. Diets directly affect the gut microbiota, which can have subsequent effects on inflammation and contribute to other chronic states. Previously we have shown that a Standard American Diet (SAD) increased immune cell activation and prolonged recovery and that a beneficial diet could reduce these negative effects. Here, male and female mice were given access to regular chow (REG), SAD, our Anti-Inflammatory Diet (AID) or a combination of SAD and AID. This latter group was modeled on the commonplace dietary pattern of healthy eating during the week (AID: Monday-Friday) and relaxed eating patterns on the weekend (SAD: Saturday-Sunday). After 14 weeks of diet consumption and an inflammatory injury, we found that the SAD prolonged and the AID promoted recovery. However, recovery was significantly delayed in those mice consuming the AID-SAD, regardless of weekly healthy diet access. In addition, fecal samples taken during the study revealed dramatic differences in microbial community composition, relative abundance of abundant bacterial phyla and alpha diversity. These data confirm the impact of diet on gut microbiota and suggest a relation between abundance of specific bacterial taxa and susceptibility to prolonged recovery from injury.
Learn More >Pain intensity is a complex and dynamic experience. A focus on assessing patients' average pain levels may miss important aspects of pain that impact functioning in daily life. In this second of 3 articles investigating alternative indices of pain intensity derived from Ecological Momentary Assessments (EMA), we examine the indices' associations with physical and psychosocial functioning. EMA data from 10 studies (2,660 patients) were reanalyzed to construct indices of Average Pain, Maximum Pain, Minimum Pain, Pain Variability, Time in High Pain, Time in Low Pain, Pain after Wake-up. Three sets of individual patient data meta-analyses examined 1) the test-retest reliability of the pain indices, 2) their convergent validity in relation to physical functioning, fatigue, depression, mental health, and social functioning, and 3) the incremental validity of alternative indices above Average Pain. Reliabilities approaching or exceeding a level of .7 were observed for all indices, and most correlated significantly with all functioning domains, with small to medium effect sizes. Controlling for Average Pain, Maximum Pain and Pain Variability uniquely predicted all functioning measures, and Time in High Pain predicted physical and social functioning. We suggest that alternative pain indices can provide new perspectives for understanding functioning in chronic pain. Perspective: Alternative summary measures of pain intensity derived from EMA have the potential to help better understand patients' pain experience. Utilizing EMA for the assessment of Maximum Pain, Pain Variability, and Time in High Pain may provide an enhanced window into the relationships between pain and patients' physical and psychosocial functioning.
Learn More >Pharmacological treatment of cluster headache constitutes the core of clinical management, but evidence is sparse. We aimed to generate insight in the existing treatment and identify associations between clinical features and treatment response.
Learn More >Migraine is associated with an increased risk of ischemic stroke. The associations are stronger in migraine with aura than in migraine without aura, in women than in men, and in younger subjects. However, the mechanisms by which migraine might increase the risk of ischemic stroke are debated.
Learn More >Most migraine patients report neck pain as part of their migraine symptomatology, but it is unknown whether triggering neck pain would induce migraine attacks. Our aim was to assess the occurrence of headache and/or neck pain after an endurance test of the neck muscles among migraineurs and controls.
Learn More >Scalable, accessible forms of behavioral therapy for migraine prevention are needed. We assessed the feasibility and acceptability of progressive muscle relaxation (PMR) delivered by a smartphone application (app) in the Primary Care setting.
Learn More >Upwards of 14% of late adolescents and young adults (AYAs) experience chronic pain; however, limited research has focused on factors specifically influencing late AYAs as they transition to adulthood. In this topical review, we propose a conceptual model of multidomain pain resilience (MDPR) in late AYAs with chronic pain that extends existing pain resilience literature, including the Ecological Resilience-Risk Model for Pediatric Chronic Pain.
Learn More >Chronic pain is a significant comorbid condition among individuals with opioid use disorder (OUD). However, due to conflicting perceptions of responsibility, structural barriers, and a lack of widely applied standards of care, it is unclear what the landscape of chronic pain management looks like in addiction medicine. Using a national opioid surveillance system, we analyzed survey data from new entrants (n=14,449) to 225 OUD treatment centers from 2013 to 2018, as well as an online survey among a subset of respondents (n=309). While chronic pain was reported by 33.4% of the sample, two-thirds of the chronic pain group (66.0%) reported their pain was not managed through their OUD treatment program, with 47% reporting worsening pain. Pain that was managed was primarily done so through pharmaceuticals (75.2%), notably as a secondary effect of medication-assisted treatment. In addition, 43.2% reported chronic pain as a primary factor in their opioid relapse. These data suggest that chronic pain is commonly reported, yet not managed by many OUD treatment programs, increasing the likelihood of opioid relapse. In order to improve poor outcomes among OUD patients, interdisciplinary collaboration/care, along with evidence-based policies or processes for quality pain management in addiction care need to be prioritized. Perspective: This article suggests chronic pain is commonly reported, yet not managed by many OUD treatment programs, increasing the likelihood of opioid relapse. In order to improve low retention and success rates among OUD patients, interdisciplinary collaboration, evidence-based policies or processes (e.g., referral) for quality pain management in addiction care need to be prioritized.
Learn More >Chronic low back pain is a common condition, with high societal costs and often ineffectual treatments. Communication between macrophages/monocytes (MØ) and sensory neurons has been implicated in various preclinical pain models. However, few studies have examined specific MØ subsets, although distinct subtypes may play opposing roles. This study used a model of low back pain/radiculopathy involving direct local inflammation of the dorsal root ganglia (DRG). Reporter mice were employed that had distinct fluorescent labels for two key MØ subsets: CCR2-expressing (infiltrating pro-inflammatory) MØ, and CX3CR1-expressing (resident) macrophages. We observed that local DRG inflammation induced pain behaviors in mice, including guarding behavior and mechanical hypersensitivity, similar to the previously described rat model. The increase in MØ in the inflamed DRG was dominated by increases in CCR2 MØ, which persisted for at least 14 days. The primary endogenous ligand for CCR2, CCL2, was upregulated in inflamed DRG. Three different experimental manipulations that reduced the CCR2 MØ influx also reduced pain behaviors: global CCR2 knockout; systemic injection of INCB3344 (specific CCR2 blocker); and intravenous injection of liposomal clodronate. The latter two treatments when applied around the time of DRG inflammation reduced CCR2 but not CX3CR1 MØ in the DRG. Together these experiments suggest a key role for the CCR2/CCL2 system in establishing the pain state in this model of inflammatory low back pain and radiculopathy. Intravenous clodronate given after pain was established had the opposite effect on pain behaviors, suggesting the role of macrophages or their susceptibility to clodronate may change with time.
Learn More >Published assays for mechanical nociception in Drosophila have led to variable assessments of behavior. Here, we fabricated, for use with Drosophila larvae, customized metal nickel-titanium alloy (nitinol) filaments. These mechanical probes are similar to the von Frey filaments used in vertebrates to measure mechanical nociception. Here, we demonstrate how to make and calibrate these mechanical probes and how to generate a full behavioral dose-response from subthreshold (innocuous or non-noxious range) to suprathreshold (low to high noxious range) stimuli. To demonstrate the utility of the probes, we investigated tissue damage-induced hypersensitivity in Drosophila larvae. Mechanical allodynia (hypersensitivity to a normally innocuous mechanical stimulus) and hyperalgesia (exaggerated responsiveness to a noxious mechanical stimulus) have not yet been established in Drosophila larvae. Using mechanical probes that are normally innocuous or probes that typically elicit an aversive behavior, we found that Drosophila larvae develop mechanical hypersensitization (both allodynia and hyperalgesia) after tissue damage. Thus, the mechanical probes and assay that we illustrate here will likely be important tools to dissect the fundamental molecular/genetic mechanisms of mechanical hypersensitivity.
Learn More >Migraine is a common neurovascular disorder affecting ~15% of the general population. Ranking second in the list of years lived with disability (YLD), people living with migraine are greatly impacted by this especially burdensome primary headache disorder. In ~30% of individuals with migraine, transient neurological symptoms occur (migraine aura) that further increase migraine burden. However, migraine burden is differential with respect to sex. Though one-year prevalences in childhood are similar, starting with puberty, migraine incidence increases at a much higher rate in females than males. Thus, migraine over the life course occurs in women three to four times more often than in men. Attacks are also more severe in women, leading to greater disability and a longer recovery period. The sex disparity in migraine is believed to be partly mediated through fluctuations in ovarian steroid hormones, especially estrogen and progesterone, although the exact mechanisms are not yet completely understood. The release of the neuropeptide calcitonin gene-related peptide (CGRP), followed by activation of the trigeminovascular system, is thought to play a key role in the migraine pathophysiology. Given the burden of migraine and its disproportionate distribution, the underlying cause(s) for the observed differences between sexes in the incidence, frequency, and intensity of migraine attacks must be better understood. Relevant biological as well as behavioral differences must be taken into account. To evaluate the scope of the existing knowledge on the issue of biological sex as well as gender differences in migraine, we conducted a systematized review of the currently available research. The review seeks to harmonize existing knowledge on the topic across the domains of biological/preclinical, clinical, and population-level research, which are traditionally synthesized and interpreted in isolation. Ultimately, we identify knowledge gaps and set priorities for further interdisciplinary and informed research on sex and gender differences as well as gender-specific therapies in migraine.
Learn More >Post-traumatic headache due to mild traumatic brain injury: Current knowledge and future directions.
Post-traumatic headache is one of the most common and persistent symptoms following mild traumatic brain injury. The objective of this narrative review is to provide an update on the diagnostic criteria, clinical presentation, epidemiology, pathophysiology, and treatment of post-traumatic headache, and to identify future research priorities.
Learn More >Preclinical studies demonstrate that sleep disruption diminishes morphine analgesia and modulates reward processing. We sought to translate these preclinical findings to humans by examining whether sleep disruption alters morphine's analgesic and hedonic properties. We randomized 100 healthy adults to receive morphine versus placebo after two nights of undisturbed sleep (US) and two nights of forced awakening (FA) sleep disruption. Sleep conditions were counterbalanced, separated by a two-week washout. The morning after both sleep conditions, we tested cold pressor pain tolerance before and 40-min after double-blind injection of .08 mg/kg morphine or placebo. The primary outcome was the analgesia index, calculated as the change in cold pressor hand withdrawal latency (HWL) before and after drug injection. Secondary outcomes were ratings of feeling "high," drug "liking," and negative drug effects. We found a significant sleep condition by drug interaction on the analgesia index (95% CI - 0.57, - 0.001). After US, subjects receiving morphine demonstrated significantly longer HWL compared to placebo (95% CI 0.23, 0.65), but not after FA (95% CI - 0.05, 0.38). Morphine analgesia was diminished threefold under FA, relative to US. After FA, females (95% CI - 0.88, - 0.05), but not males (95% CI - 0.23, 0.72), reported decreased subjective "high" effects compared to US. After FA, females (95% CI 0.05, 0.27), but not males (95% CI - 0.10, 0.11), administered morphine reported increased negative drug effects compared to US. These data demonstrate that sleep disruption attenuates morphine analgesia in humans and suggest that sleep disturbed males may be at greatest risk for problematic opioid use.
Learn More >Work absenteeism due to chronic non-malignant pain (CNMP) is a major societal and individual cause of concern that requires effective treatments.
Learn More >To study the efficacy and safety of fasinumab in moderate-to-severe, chronic low back pain (CLBP).
Learn More >Social and interpersonal factors impact the trajectory of chronic pain. We previously developed and validated a 2-factor, 7-item measure to assess interpersonal factors, including relationship guilt and worry and difficulty prioritizing self-care in chronic pain. Here, we confirm the factor structure and examine the sex invariance of the two-factor structure of the CARE Scale-7.
Learn More >Endometriosis, affecting approximately 176 million adults and adolescents worldwide, is a debilitating condition in which uterine tissue grows outside the uterus. The condition costs the US economy approximately $78 billion annually in pain-related disability. By understanding the neural underpinnings of endometriosis-associated pain (EAP) and risk factors for chronification, translational research methods could lessen diagnostic delays and maximize successful pain remediation. This can be accomplished by the novel use of a known method, offset analgesia (OA), to better elucidate the neural mechanisms that may contribute to and maintain EAP. This commentary will provide justification and rationale for the use of OA in the study of EAP.
Learn More >The pathophysiology of headaches associated with rhinosinusitis is poorly known. Since the generation of headaches is thought to be linked to the activation of intracranial afferents, we used an animal model to characterise spinal trigeminal neurons with nociceptive input from the dura mater and paranasal sinuses.
Learn More >Acceptance and commitment therapy (ACT) is a behavioral health intervention with strong empirical support for chronic pain but, to date, widespread dissemination is limited. Digital solutions improve access to care and can be integrated into patients' everyday lives.
Learn More >Depression, fatigue, and pain commonly co-occur in multiple sclerosis (MS) and are positively associated with one another. However, it is unclear whether treatment-related improvement in one of these symptoms is associated with improvements in the other two symptoms.
Learn More >The aim of this study was to describe the information access behaviours of clinicians involved in pain management with respect to their use of a pain evidence resource and to determine the areas of professional differences.
Learn More >Transient receptor potential (TRP) channels are a superfamily of non-selective cation channels that act as polymodal sensors in many tissues throughout mammalian organisms. In the context of ion channels, they are unique for their broad diversity of activation mechanisms and their cation selectivity. TRP channels are involved in a diverse range of physiological processes including chemical sensing, nociception, and mediating cytokine release. They also play an important role in the regulation of inflammation through sensory function and the release of neuropeptides. In this review, we discuss the functional contribution of a subset of TRP channels (TRPV1, TRPV4, TRPM3, TRPM8, and TRPA1) that are involved in the body's immune responses, particularly in relation to inflammation. We focus on these five TRP channels because, in addition to being expressed in many somatic cell types, these channels are also expressed on peripheral ganglia and nerves that innervate visceral organs and tissues throughout the body. Activation of these neural TRP channels enables crosstalk between neurons, immune cells, and epithelial cells to regulate a wide range of inflammatory actions. TRP channels act either through direct effects on cation levels or through indirect modulation of intracellular pathways to trigger pro- or anti-inflammatory mechanisms, depending on the inflammatory disease context. The expression of TRP channels on both neural and immune cells has made them an attractive drug target in diseases involving inflammation. Future work in this domain will likely yield important new pathways and therapies for the treatment of a broad range of disorders including colitis, dermatitis, sepsis, asthma, and pain.
Learn More >While the prognosis of patients with Ewing sarcoma (EwS) is improving, little is known about the frequency of pain and its risk factors in survivors of EwS. This study aims to analyse the prevalence and risk factors of pain and its predictive value for recurrence.
Learn More >Sickle cell disease (SCD) is a hemoglobinopathy affecting multiple organs and featuring acute and chronic pain. Purkinje cell damage and hyperalgesia have been demonstrated in transgenic sickle mice. Purkinje cells are associated with movement and neural function which may influence pain. We hypothesized that Purkinje cell damage and/or chronic pain burden provoke compensatory gait changes in sickle mice. We found that Purkinje cells undergoe increased apoptosis as shown by caspase-3 activation. Using an automated gait measurement system, MouseWalker, we characterized spatiotemporal gait characteristics of humanized transgenic BERK sickle mice in comparison to control mice. Sickle mice showed alteration in stance instability and dynamic gait parameters (walking speed, stance duration, swing duration and specific swing indices). Differences in stance instability may reflect motor dysfunction due to damaged Purkinje cells. Alterations in diagonal and all stance indices indicative of hesitation during walking may originate from motor dysfunction and/or arise from fear and/or anticipation of movement-evoked pain. We also demonstrate that stance duration, diagonal swing indices and all stance indices correlate with both mechanical and deep tissue hyperalgesia, while stance instability correlates with only deep tissue hyperalgesia. Therefore, objective analysis of gait in SCD may provide insights into neurological impairment and pain states.
Learn More >Fibromyalgia syndrome (FM) is a complex disease that is mainly characterised by chronic widespread pain, fatigue and sleep disturbances and may be precipitated or worsened by many stressors. The aim of this study was to observe the behaviour of FM symptoms during the course of coronavirus disease 2019 (COVID-19).
Learn More >The key role of pro-inflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) is strongly supported by the observation that their blockage is effective in the treatment of these diseases. Indeed, blockade of cytokine signal transduction mechanisms, including the JAK-STAT pathway, may be critical in the treatment of RA and PsA. The Janus kinase (JAK) inhibitors tofacitinib and baricitinib target JAKs with high potency and have a well-established rationale for clinical therapeutic use in RA and PsA by affecting multiple cytokines involved in both development and propagation of the disease. Nociceptive responses are also important to consider in the treatment RA and PsA. In this regard, cytokines have also been implicated in modulation of pain and nociception and the JAK/STAT pathway is receiving increasing attention in modulation of nociceptive responses given to its clear role in cytokine signalling. Therefore, inhibition of JAK/STAT pathway with specific JAK inhibitors has the potential to modulate pain in patients with RA and PsA. Data from randomised controlled trials and real-world settings on large numbers of patients with RA (tofacitinib and baricitinib) and randomised controlled trials in patients with PsA (tofacitinib) have shown that a rapid effect on the pain component in these diseases is observed. Thus, it can be hypothesised that JAK inhibitors may have a dual therapeutic role by modulating inflammation and nociception, which leads to clinical benefits including reduction of pain beyond that related to inflammation. The present review will overview the impact of pain in patients with rheumatic disease and the physiological basis of modulating nociceptive pain. Current knowledge about the role of cytokines in mediation of pain and the involvement of the JAK/STAT pathway in modulating nociceptive responses will then be summarised, followed by an analysis of clinical data on pain modulation by JAK inhibitors in the treatment of RA and PsA.
Learn More >Peripheral nerve injury often leads to neuropathic pain. In the present study, we assessed the role of liver x receptor alpha (LXRα), an oxysterol regulated nuclear transcription factor that promotes reverse cholesterol transport and alternative (M2) macrophage activation, in the development of neuropathic pain. We found that compared to WT mice, in LXRα knockout mice the development of mechanical allodynia following sciatic nerve crush was accelerated and the duration was prolonged. Furthermore, the expression of M1-like macrophage marker iNOS and M1-like macrophages inducer hydrogen peroxide (H2O2) was increased, whereas expression of M2 macrophage marker arginase-1 (Arg-1) and interleukin-10 (IL-10) was reduced in the sciatic nerve of LXRα knockout mice. Moreover, peri-sciatic administration of LXRs agonist GW3965, immediately after the nerve crush, into wild type mice, suppressed the mechanical allodynia induced by crush injury. GW3965 also suppressed the expression of iNOS and production of H2O2 in the injured nerve and enhanced the expression of IL-10 and Arg-1. Importantly, peri-sciatic administration of IL-10 neutralization antibody prevented the alleviating effect of GW3965 on mechanical allodynia. Altogether, these results indicates that the lack of LXRα in the sciatic nerve results in an augmented inflammatory profile of macrophages, which ultimately speed up the development of neuropathic pain and dampen its recovery following nerve injury. Activation of LXRα by its agonist might rebalance the neuroprotective and neurotoxic macrophage phenotypes, and thus alleviate the neuropathic pain behavior.
Learn More >This is a prospective, blinded, case-control study of patients with chronic pain using body diagrams and colored markers to show the distribution and quality of pain and sensory symptoms (aching, burning, tingling, numbness, and sensitivity to touch) experienced in affected body parts.
Learn More >Central sensitization and impaired conditioned pain modulation (CPM) response have been reported to contribute to migraine progression. Migraine patients can present with allodynia possibly attributed to increased sensitivity of peripheral ends of nociceptors with both peripheral and central sensitization. Occipital nerve stimulation (ONS) works by stimulating the distal branches of C1, C2 and C3 possibly altering the nociceptive traffic to the trigemino-cervical complex, brainstem and supranuclear connections.
Learn More >Chronic pain is one of the most prevalent causes of disability worldwide, and digital interventions may be one of the ways to meet this need. Randomised controlled trials have demonstrated that digital interventions can be effective in treating chronic pain. This study aimed to establish the clinical effectiveness of a web-based pain management programme (PMP), specifically whether it would lead to improved clinical outcomes and reduced health care costs in a real-world clinical setting.
Learn More >Evidence suggests a bidirectional association between migraine and depression in individuals and in twins. However, whether a bidirectional association between migraine and depression also occurs among siblings (probands and unaffected nontwin siblings) remains unknown.
Learn More >The United States (US) population consumes an estimated 68% of the world's prescribed opioids each year, and over 2 million adults in the US suffer from an opioid use disorder. Although chronic pain populations are among the highest risk segments of the general population for opioid misuse and dependence, there is little understanding of individual risk characteristics that may contribute to greater risk for these outcomes among this group. The present investigation explored the concurrent role of anxiety sensitivity and pain intensity and their interaction in relation to opioid misuse and dependence among 429 adults with chronic pain (73.9% female, M = 38.32 years, SD = 11.07). Results revealed that both anxiety sensitivity and pain intensity were associated with opioid misuse and dependence. There was no evidence of an interaction for either outcome. Post-hoc analyses indicated that of the lower-order anxiety sensitivity facets, physical and mental incapacitation concerns contributed to variance in opioid misuse and only mental incapacitation concerns contributed to variance in opioid dependence. Overall, the current findings suggest the importance of assessing anxiety sensitivity in screening for opioid-related problems among persons with chronic pain, as it may represent a distinct pathway to poorer opioid-related outcomes among this group.
Learn More >Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic urological condition characterised by urinary urgency, frequency and pelvic pain, that significantly impacts the quality of life for ∼5% of women. Bladder sensation is coordinated by primary afferent sensory neurons that innervate the bladder wall, translating bladder stretch into signals that travel to the brain via the spinal cord. Whilst the pathophysiology of IC/BPS remains unknown, an increase in the permeability of the bladder urothelium has been proposed as an initiating cause. Here we experimentally increased bladder permeability and tracked bladder afferent sensitivity for up to 28 days. We found that one day after increasing bladder epithelial permeability with bladder infusion of protamine sulfate, mechanosensitive bladder afferents exhibited significant hypersensitivity to bladder filling. This mechanical hypersensitivity was characterised by significantly increased peak afferent firing rates and a decrease in the activation threshold of individual afferents. Bladder afferent hypersensitivity occurred in the absence of inflammation and changes in bladder muscle compliance, indicating a direct sensitisation of peripheral afferent endings. Bladder afferent mechanosensitive responses to distension returned to control levels by day 7 post-protamine sulfate treatment and remained at control levels at 28-days post-treatment. Here we demonstrate, contrary to the prevailing hypothesis, that increased bladder permeability alone does not induce chronic bladder afferent sensitisation. Whilst experimentally induced changes in bladder permeability are able to induce transient bladder afferent hypersensitivity in the absence of inflammation, highly regulated homeostatic mechanisms exist to rapidly repair the urothelial barrier and normalise bladder afferent mechanosensitivity. Together, these data suggest that additional pathophysiology is required to induce chronic bladder dysfunction.
Learn More >The Revised Short McGill Pain Questionnaire Version-2 (SF-MPQ-2) is a multidimensional outcome measure designed to capture, evaluate and discriminate pain from neuropathic and non-neuropathic sources. A recent systematic review found insufficient psychometric data with respect to musculoskeletal (MSK) health conditions. This study aimed to describe the reproducibility (test-retest reliability and agreement) and internal consistency of the SF-MPQ-2 for use among patients with musculoskeletal shoulder pain.
Learn More >Neuropathic pain is frequently associated with anxiety and major depressive disorders, which considerably impact the overall patient experience. Favoring GABAergic inhibition through the pain matrix has emerged as a promising strategy to restore proper processing of nociceptive and affective information in neuropathic pain states. In this context, the non-benzodiazepine anxiolytic etifoxine (EFX), known to amplify GABAergic inhibition through positive modulation of GABA receptors and neurosteroidogenesis, presents several advantages. Therefore, we sought to investigate the preclinical therapeutic potential of EFX on the somatosensory and affective components of neuropathic pain. Here, we used a murine model in which neuropathic pain was induced by the implantation of a compressive cuff around the sciatic nerve (mononeuropathy). We showed that the intraperitoneal EFX treatment for five consecutive days (50 mg/kg) relieved mechanical allodynia in a sustained manner. Besides its effect on evoked mechanical hypersensitivity, EFX also alleviated aversiveness of ongoing pain as well as anxiodepressive-like consequences of neuropathic pain following cuff-induced mononeuropathy. This effect was also seen 12 weeks after induction of the neuropathy when allodynia was no longer present. Analgesic and neuroprotective actions of EFX were also seen by the absence of neuropathic pain symptoms if a second sciatic nerve constriction injury was applied to the contralateral hindpaw. Mass spectrometry analysis revealed a normalization of brainstem serotonin levels in EFX-treated animals and an increase in norepinephrine. This study suggests that EFX presents promising therapeutic potential for the relief of both somatosensory and affective consequences of neuropathic pain, a beneficial effect that is likely to involve monoamine descending controls.
Learn More >The aim of the study was to investigate patient satisfaction amongst academic pain management centers and associated factors.
Learn More >FSC231 can alleviate paclitaxel-induced neuralgia by inhibiting PICK1 and affecting related factors.
To explore the inhibitory effect of FSC231, a PDZ domain inhibitor of protein interacting with C kinase 1 (PICK1), on paclitaxel induced neuralgia and its possible pathways.
Learn More >Use of parenteral opioids is a major risk factor for postoperative nausea and vomiting. Conventional opioids bind to µ-opioid receptors (MOR), stimulate both the G-protein signaling (achieving analgesia); and the β-arrestin pathway (associated with opioid-related adverse effects). Oliceridine, a next-generation IV opioid, is a G-protein selective MOR agonist, with limited recruitment of β-arrestin. In two randomized, placebo- and morphine-controlled phase 3 studies of patients with moderate-to-severe acute pain following bunionectomy or abdominoplasty, oliceridine at demand doses of 0.1, 0.35, and 0.5 mg provided rapid and sustained analgesia vs. placebo with favorable gastrointestinal (GI) tolerability. In this exploratory analysis, we utilized a clinical endpoint assessing gastrointestinal tolerability, "complete GI response" defined as the proportion of patients with no vomiting and no use of rescue antiemetic to characterize the GI tolerability profile of oliceridine vs. morphine.
Learn More >Chronic pain (CP) and cognitive decline (CD) are costly, challenging to treat, highly prevalent among older adults, and worsen each other over time. We are iteratively developing Active-Brains-Fitbit (AB-F), a live video program for older adults with CP and CD that teaches mind-body skills and gradual increases in step count aided by a Fitbit. AB-F has demonstrated feasibility, acceptability, and signals of improvement in emotional, physical, and cognitive function when delivered in-person to this population.
Learn More >Cisplatin and oxaliplatin are treatment options for a variety of cancer types. While highly efficient in killing cancer cells, both chemotherapeutics cause severe side effects, e.g., peripheral neuropathies. Using a cell viability assay, a mitochondrial stress assay, and live-cell imaging, the effects of cis- or oxaliplatin on the mitochondrial function, reactive oxygen species (ROS) production, and mitochondrial and cytosolic calcium concentration of transient receptor potential ankyrin 1 (TRPA1)- or vanilloid 1 (TRPV1)-positive dorsal root ganglion (DRG) neurons of adult Wistar rats were determined. Mitochondrial functions were impaired after exposure to cis- or oxaliplatin by mitochondrial respiratory chain complex I-III inhibition. The basal respiration, spare respiratory capacity, and the adenosine triphosphate (ATP)-linked respiration were decreased after exposure to 10 µM cis- or oxaliplatin. The ROS production showed an immediate increase, and after reaching the peak, ROS production dropped. Calcium imaging showed an increase in the cytosolic calcium concentration during exposure to 10 µM cis- or oxaliplatin in TRPA1- or TRPV1-positive DRG neurons while the mitochondrial calcium concentration continuously decreased. Our data demonstrate a significant effect of cis- and oxaliplatin on mitochondrial function as an early event of platinum-based drug exposure, suggesting mitochondria as a potential target for preventing chemotherapy-induced neuropathy.
Learn More >Introduction Cluster headache [CH] is a severely disabling trigeminal autonomic cephalalgia [TAC]. Approximately 1 in 1,000 adults are affected by CH. Calcitonin gene related peptide [CGRP] is an important mediator in the pathophysiology of CH. Galcanezumab is a monoclonal antibody with an affinity for the CGRP peptide, FDA approved for prevention of episodic CH. Areas covered Search words queried were 'cluster headache', 'cluster headache and CGRP', 'cluster headache and galcanezumab'. Over 99 articles in Pubmed and prescribing information for galcanezumab was reviewed. Some of the data pertaining to CH trials with fremanezumab were reviewed using clinical trials.org. Expert opinion Galcanezumab has shown benefit in decreasing weekly frequency of CH attacks across week 1 through week 3 in patients with CH; 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (95% confidence interval, 0.2 to 6.7; P = 0.04). It has a favorable risk benefit ratio. The prevention of CH with CGRP inhibition represents a novel advance for a condition with a significant unmet need. The negative trial results of galcanezumab for chronic cluster headache [CCH] may be due to the refractory nature and sheds light on the critical need to investigate the underlying biology and therapeutic options.
Learn More >Pain sensitivity may determine the risk, severity, prognosis, and efficacy of treatment of clinical pain. Magnetic resonance imaging studies have linked thermal pain sensitivity to changes in brain structure. However, the neural correlates of mechanical pain sensitivity remain to be clarified through investigation of direct neural activities on the resting-state cortical oscillation and synchrony.
Learn More >Endometriosis is an estrogen-dependent gynecological disease, with an associated chronic inflammatory component, characterized by the presence of endometrial tissue outside the uterine cavity. Its predominant symptom is pain, a condition notably altering the quality of life of women with the disease. This review is intended to exhaustively gather current knowledge on purinergic signaling in endometriosis-associated pain. Altered extracellular ATP hydrolysis, due to changes in ectonucleotidase activity, has been reported in endometriosis; the resulting accumulation of ATP in the endometriotic microenvironment points to sustained activation of nucleotide receptors (P2 receptors) capable of generating a persistent pain message. P2X3 receptor, expressed in sensory neurons, mediates nociceptive, neuropathic, and inflammatory pain, and is enrolled in endometriosis-related pain. Pharmacological inhibition of P2X3 receptor is under evaluation as a pain relief treatment for women with endometriosis. The role of other ATP receptors is also discussed here, e.g., P2X4 and P2X7 receptors, which are involved in inflammatory cell-nerve and microglia-nerve crosstalk, and therefore in inflammatory and neuropathic pain. Adenosine receptors (P1 receptors), by contrast, mainly play antinociceptive and anti-inflammatory roles. Purinome-targeted drugs, including nucleotide receptors and metabolizing enzymes, are potential non-hormonal therapeutic tools for the pharmacological management of endometriosis-related pain.
Learn More >Chemokines and receptors have been implicated in the pathogenesis of chronic pain. Here, we report that spinal nerve ligation (SNL) increased CXCR3 expression in dorsal root ganglion (DRG) neurons, and intra-DRG injection of Cxcr3 shRNA attenuated the SNL-induced mechanical allodynia and heat hyperalgesia. SNL also increased the mRNA levels of CXCL9, CXCL10, and CXCL11, whereas only CXCL10 increased the number of action potentials (APs) in DRG neurons. Furthermore, in Cxcr3 mice, CXCL10 did not increase the number of APs, and the SNL-induced increase of the numbers of APs in DRG neurons was reduced. Finally, CXCL10 induced the activation of p38 and ERK in ND7-23 neuronal cells and DRG neurons. Pretreatment of DRG neurons with the P38 inhibitor SB203580 decreased the number of APs induced by CXCL10. Our data indicate that CXCR3, activated by CXCL10, mediates p38 and ERK activation in DRG neurons and enhances neuronal excitability, which contributes to the maintenance of neuropathic pain.
Learn More >Stress is a known trigger for flares of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS); however, this process is not well understood. Here, we find that restraint stress in mice leads to signs of diarrhea, fecal dysbiosis, and a barrier defect via the opening of goblet-cell associated passages. Notably, stress increases host immunity to gut bacteria as assessed by immunoglobulin A (IgA)-bound gut bacteria. Stress-induced microbial changes are necessary and sufficient to elicit these effects. Moreover, similar to mice, many diarrhea-predominant IBS (IBS-D) patients from two cohorts display increased antibacterial immunity as assessed by IgA-bound fecal bacteria. This antibacterial IgA response in IBS-D correlates with somatic symptom severity and was distinct from healthy controls or IBD patients. These findings suggest that stress may play an important role in patients with IgA-associated IBS-D by disrupting the intestinal microbial community that alters gastrointestinal function and host immunity to commensal bacteria.
Learn More >Meditation has been shown to improve outcomes for chronic pain by increasing patients' awareness of their own bodies. Some patients have an innate ability to leverage their mind-body connection, and this interoceptive awareness may aid them in garnering pain relief. We explored whether spinal cord stimulation (SCS) patients with greater innate awareness had better outcomes.
Learn More >The aims of the present systematic review were to explore the prevalence of migraine with anxiety exclusively and determine if and why there are likely to be differences across genders. Migraine is a very common neurological disorder and cause of productive disability worldwide that is more frequent in women of childbearing age than males. Previous studies have frequently demonstrated comorbidity of migraine and other psychiatric disorders. Although the prevalence of migraine across gender is well-established there are few if any systematic reviews on the prevalence of migraine comorbidity with anxiety cross-genders. The present systematic review included prevalence studies, clinic-based and cohort studies that reported the frequency of migraine with anxiety within the study sample. Eleven studies were included in the review after screening by two independent reviewers. Studies included participants who were 16 years and older diagnosed with migraine. The main findings of this review indicated that anxiety is a major comorbidity of migraine worldwide, with a wide range (16-83%) of prevalence and a mean of ~43% of patients experiencing comorbid symptoms. Subjective anxiety symptoms appear to be greater among males with migraine than females which could be attributable to both environmental and/or hormonal and genetic predispositions. The results reemphasize the high prevalence of migraine and comorbid anxiety symptoms worldwide while showing that although migraine is far more prevalent among women in general co-morbidity of migraine with anxiety unfolds a different gender difference. The results highlight the significance of exploring the impact of existing and pre-existing comorbid conditions of patients with migraines and further consideration into their diagnostic and treatment strategies.
Learn More >The present study was designed to investigate whether the antinociceptive effect of bone marrow-derived mesenchymal stem/stromal cells (MSC) during oxaliplatin (OXL)-induced sensory neuropathy is related to antioxidant properties.
Learn More >Interstitial cystitis/bladder pain syndrome (IC/BPS) is a type of chronic bladder inflammation characterized by increased voiding frequency, urgency and pelvic pain. The sensitization of bladder afferents is widely regarded as one of the pathophysiological changes in the development of IC/BPS. There is evidence that adenosine A receptors are involved in regulating the sensitization of sensory afferents. However, the effect of adenosine A receptors on cystitis remains unknown. In the present study, a rat model of chronic cystitis was established by intraperitoneal injection with cyclophosphamide (CYP). Cystometry and behavioral tests were performed to investigate bladder micturition function and nociceptive pain. The rats with chronic cystitis showed symptoms of bladder overactivity, characterized by an increase in bladder voiding frequency and voiding pressure. CYP treatment significantly increased the expression of the A receptor in bladder afferent fibers and dorsal root ganglion (DRG) neurons. The A receptor antagonist ZM241385 prevented bladder overactivity and hyperalgesia elicited by CYP-induced cystitis. In addition, the A receptor and TRPV1 were coexpressed on DRG neurons. The TRPV1 antagonist capsazepine blocked bladder overactivity induced by the A receptor agonist CGS21680. In contrast, ZM241385 significantly inhibited the capsaicin-induced increase in intracellular calcium concentration in DRG neurons. These results suggest that suppression of adenosine A receptors in bladder afferents alleviates bladder overactivity and hyperalgesia elicited by CYP-induced cystitis in rats by inhibiting TRPV1, indicating that the adenosine A receptor in bladder afferents is a potential therapeutic target for the treatment of IC/BPS.
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Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain.
Dysfunction in regulation of mRNA translation is an increasingly recognized characteristic of many diseases and disorders, including cancer, diabetes, autoimmunity, neurodegeneration, and chronic pain. Approximately 50 million adults in the United States experience chronic pain. This economic burden is greater than annual costs associated with heart disease, cancer, and diabetes combined. Treatment options for chronic pain are inadequately efficacious and riddled with adverse side effects. There is thus an urgent unmet need for novel approaches to treating chronic pain. Sensitization of neurons along the nociceptive pathway causes chronic pain states driving symptoms that include spontaneous pain and mechanical and thermal hypersensitivity. More than a decade of preclinical research demonstrates that translational mechanisms regulate the changes in gene expression that are required for ongoing sensitization of nociceptive sensory neurons. This review will describe how key translation regulation signaling pathways, including the integrated stress response, mammalian target of rapamycin, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase-interacting kinases, impact the translation of different subsets of mRNAs. We then place these mechanisms of translation regulation in the context of chronic pain states, evaluate currently available therapies, and examine the potential for developing novel drugs. Considering the large body of evidence now published in this area, we propose that pharmacologically manipulating specific aspects of the translational machinery may reverse key neuronal phenotypic changes causing different chronic pain conditions. Therapeutics targeting these pathways could eventually be first-line drugs used to treat chronic pain disorders. SIGNIFICANCE STATEMENT: Translational mechanisms regulating protein synthesis underlie phenotypic changes in the sensory nervous system that drive chronic pain states. This review highlights regulatory mechanisms that control translation initiation and how to exploit them in treating persistent pain conditions. We explore the role of mammalian/mechanistic target of rapamycin and mitogen-activated protein kinase-interacting kinase inhibitors and AMPK activators in alleviating pain hypersensitivity. Modulation of eukaryotic initiation factor 2α phosphorylation is also discussed as a potential therapy. Targeting specific translation regulation mechanisms may reverse changes in neuronal hyperexcitability associated with painful conditions.
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