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To assess the long-term safety, tolerability, and efficacy of fremanezumab, a fully humanized monoclonal antibody approved for the preventive treatment of migraine.
Learn More >Neuropathic pain is a debilitating public health concern for which novel non-narcotic therapeutic targets are desperately needed. Using unbiased transcriptomic screening of the dorsal horn spinal cord after nerve injury we have identified that Gpr183 (Epstein-Barr induced gene 2 [EBI2]) is upregulated after chronic constriction injury (CCI) in rats. GPR183 is a chemotactic receptor known for its role in the maturation of B cells and the endogenous ligand is the oxysterol, 7α,25-dihydroxycholesterol (7α,25-OHC). The role of GPR183 in the central nervous system is not well characterized and its role in pain is unknown. The profile of commercially available probes for GPR183 limits their use as pharmacological tools to dissect the roles of this receptor in pathophysiological settings. Using in silico modeling, we have screened a library of 5 million compounds to identify several novel small-molecule antagonists of GPR183 with nanomolar potency. These compounds are able to antagonize 7α,25-OHC-induced calcium mobilization in vitro with IC50 values below 50nM. In vivo intrathecal injections of these antagonists during peak pain after CCI surgery reversed allodynia in male and female mice. Acute intrathecal injection of the GPR183 ligand, 7α,25-OHC in naïve mice induced dose-dependent allodynia. Importantly, this effect was blocked using our novel GPR183 antagonists, suggesting spinal GPR183 activation as pro-nociceptive. These studies are the first to reveal a role for GPR183 in neuropathic pain and identify this receptor as a potential target for therapeutic intervention. We have identified several novel GPR183 antagonists with nanomolar potency. Using these antagonists, we have demonstrated that GPR183 signaling in the spinal cord is pro-nociceptive. These studies are the first to reveal a role for GPR183 in neuropathic pain and identify it as a potential target for therapeutic intervention.
Learn More >One in five patients undergoing total knee arthroplasty (TKA) experience unchanged or worse pain and physical function 1 year after surgery. Identifying risk factors for unfavourable outcomes is necessary to develop tailored interventions to minimise risk. There is a need to review more current literature with updated methodology that addresses the limitations of earlier systematic reviews and meta-analyses. We present a Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols compliant protocol for a systematic review and meta-analysis of predictors of chronic pain and impaired function after TKA.
Learn More >Recent advances in our understanding of the pathophysiology of atopic dermatitis (AD) have revealed that skin microbiome dysbiosis plays an important role in the disease. In this review, we describe how changes in the structure and function of the microbiome are involved in the pathogenesis of AD. We highlight recent data showing that differential changes in microbial diversity, both within and across communities from different body habitats (including the skin, gut, and oral mucosa), are associated with the development and severity of AD. We also describe recent evidence demonstrating that the metabolic activity of the skin microbiome can act as a regulator of inflammation, with alterations in the level of a skin microbiome-derived tryptophan metabolite, indole-3-aldehyde (IAId), being shown to play a role in AD. The various mechanisms by which interactions between the microbiome and components of the non-histaminergic pathway result in itch in AD are also discussed.
Learn More >Occipital nerve stimulation (ONS) is used to treat therapy-resistant chronic migraine. Clinical use has resulted in a wide intraindividual and interindividual variation of clinical efficacy. The aim of this study was to analyze a potential relationship between sociodemographic variables, headache parameters, perceived sensory quality, perceived sensory location, as well as clinical efficacy.
Learn More >The venom of jellyfish triggers severe dermal pain along with inflammation and tissue necrosis, and occasionally, induces internal organ dysfunction. However, the basic mechanisms underlying its cytotoxic effects are still unknown. Here, we report one of the mechanisms involved in peripheral pain modulation associated with inflammatory and neurotoxic oxidative signaling in rats using the venom of jellyfish, Chrysaora pacifica (CpV). This jellyfish is identified by brown tentacles carrying nematocysts filled with cytotoxic venom that induces severe pain, pruritus, tentacle marks, and blisters. The subcutaneous injection of CpV into rat forepaws in behavioral tests triggered nociceptive response with a decreased threshold for mechanical pain perception. These responses lasted up to 48 h and were completely blocked by verapamil and TTA-P2, T-type Ca channel blockers, or HC030031, a transient receptor potential cation ankyrin 1 (TRPA1) channel blocker, while another Ca channel blocker, nimodipine, was ineffective. Also, treatment with Ca chelators (EGTA and BaptaAM) significantly alleviated the CpV-induced pain response. These results indicate that CpV-induced pain modulation may require both Ca influx through the T-type Ca channels and activation of TRPA1 channels. Furthermore, CpV induced Ca-mediated oxidative neurotoxicity in the dorsal root ganglion (DRG) and cortical neurons dissociated from rats, resulting in decreased neuronal viability and increased intracellular levels of ROS. Taken together, CpV may activate Ca-mediated oxidative signaling to produce excessive ROS acting as an endogenous agonist of TRPA1 channels in the peripheral terminals of the primary afferent neurons, resulting in persistent inflammatory pain. These findings provide strong evidence supporting the therapeutic effectiveness of blocking oxidative signaling against pain and cytotoxicity induced by jellyfish venom.
Learn More >Alterations beyond joint inflammation such as changes in dorsal horn (DH) excitability contribute to pain in inflammatory arthritis (IA). More complete understanding of specific underlying mechanisms will be important to define novel targets for the treatment of IA pain. Pre-clinical models are useful, but relevant pain assays are vital for successful clinical translation. For this purpose, a method is presented to assess movement-induced pain-related behaviour changes that was subsequently used to investigate DH disinhibition in IA.
Learn More >Endometriosis is a chronic inflammatory disease defined as the presence of endometrial tissue outside the uterus that causes pelvic pain and infertility. We used the Global Burden of Disease Study (GBD) 2017 to comprehensively analyze the burden of endometriosis between 1990 and 2017. DisMod-MR 2.1 was used to estimate the incidence and prevalence in some countries/territories with sparse or absent data. Annual percent changes were calculated to quantify endometriosis burden estimate trends. Furthermore, the sociodemographic index (SDI) was used to assess the relationship between endometriosis burden estimates and development level. Between 1990 and 2017, endometriosis age-standardized incidence and prevalence and years of life lived with disability (YLDs) decreased globally by 0.21% (95% confidence interval (CI): -0.23% to -0.20%), 0.29% (95% CI: -0.31% to -0.28%), and 0.28% (95% CI: -0.30% to -0.27%) per year, respectively. Apart from the high SDI quintiles with increasing trends of endometriosis incidence rate, prevalence rate, and YLDs, decreasing trends were observed in all SDI quintiles for all burden estimates. In conclusion, it appears that all endometriosis burden estimates have decreased globally between 1990 and 2017. However, these results are based on limited data and highlight the need for increased data collection on the incidence and prevalence of endometriosis.
Learn More >In 2015, the United States of America (USA) Department of Health and Human Services (HHS) released an issue brief that addressed opioid addiction, opioid overdoses, and opioid-related deaths as a public health concern within the country. After collaboration with state and stakeholder organizations, the HHS identified three target initiatives aimed to mitigate the negative consequences of opioid use within the USA. One initiative included implementation of guidelines to help reduce inappropriate opioid prescribing with a goal to reduce morbidity and mortality. The aim of this commentary is to discuss the misapplication and unintended consequences of the USA CDC Guideline for Prescribing Opioids for Chronic Pain.
Learn More >The effects of exercise on mechanical hyperalgesia, joint contracture, and muscle injury resulting from immobilization are not completely understood. This study aimed to investigate the effects of cyclic stretching on these parameters in a rat model of chronic post-cast pain (CPCP). Seventeen 8-week-old Wistar rats were randomly assigned to (1) control group, (2) immobilization (CPCP) group, or (3) immobilization and stretching exercise (CPCP+STR) group. In the CPCP and CPCP+STR groups, both hindlimbs of each rat were immobilized in full plantar flexion with a plaster cast for a 4-week period. In the CPCP+STR group, cyclic stretching exercise was performed 6 days/week for 2 weeks, beginning immediately after cast removal prior to reloading. Although mechanical hyperalgesia in the plantar skin and calf muscle, ankle joint contracture, and gastrocnemius muscle injury were observed in both immobilized groups, these changes were significantly less severe in the CPCP+STR group than in the CPCP group. These results clearly demonstrate the beneficial effect of cyclic stretching exercises on widespread mechanical hyperalgesia, joint contracture, and muscle injury in a rat model of CPCP.
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