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Evidence suggests that blunted reward responsiveness may account for poor clinical outcomes in both opioid use disorder (OUD) and chronic pain. Understanding how individuals with OUD and comorbid chronic pain (OUD+CP) respond to rewards is, therefore, of clinical interest because it may reveal a potential point of behavioral intervention.
Learn More >VVZ-149 is a small molecule that both inhibits the glycine transporter type 2 and the serotonin receptor 5 hydroxytryptamine 2 A. In a randomized, parallel-group, and double-blind trial (NCT02844725), we investigated the analgesic efficacy and safety of VVZ-149 Injections, which is under clinical development as a single-use injectable product for treating moderate to severe postoperative pain.
Learn More >Peripheral nerve injury induces long-term pro-inflammatory responses in spinal cord glial cells that facilitate neuropathic pain, but the identity of endogenous cells that resolve spinal inflammation has not been determined. Guided by single-cell RNA sequencing (scRNA-seq), we found that MRC1 spinal cord macrophages proliferated and upregulated the anti-inflammatory mediator Cd163 in mice following superficial injury (SI; nerve intact), but this response was blunted in nerve-injured animals. Depleting spinal macrophages in SI animals promoted microgliosis and caused mechanical hypersensitivity to persist. Conversely, expressing Cd163 in spinal macrophages increased Interleukin 10 expression, attenuated micro- and astrogliosis, and enduringly alleviated mechanical and thermal hypersensitivity in nerve-injured animals. Our data indicate that MRC1 spinal macrophages actively restrain glia to limit neuroinflammation and resolve mechanical pain following a superficial injury. Moreover, we show that spinal macrophages from nerve-injured animals mount a dampened anti-inflammatory response but can be therapeutically coaxed to promote long-lasting recovery of neuropathic pain.
Learn More >The mechanism underlying the high incidence of remifentanil-induced postoperative hyperalgesia is unclear. Also, no effective prevention method exists. Inflammatory pain-related studies showed that P2 × 4 purinergic receptors (P2X4Rs) in the dorsal horn of the spinal cord and dorsal root ganglia are essential for maintaining allodynia caused by inflammation. However, little is known about its role in opioid-induced hyperalgesia. This study aimed to determine the role of P2X4R and related signaling pathways in the remifentanil-induced postoperative hyperalgesia (RIH) model. The study simulated the remifentanil infusion and surgical incision during general anesthesia. The mRNA and protein expression level of P2X4R in rats with RIH model increased from 2 h to 48 h after the surgery. The administration of P2X4R inhibitors prevented the occurrence of RIH, resulting in a reduction in mechanical and thermal pain. Moreover, P2X4R was involved in RIH in male and female rats, indicating no sex-specific difference. P2X4R also increased the expression of AMPA receptor subunit GluA1 in a brain-derived neurotrophic factor (BDNF) / tyrosine receptor kinase B (TrkB) dependent manner. The results from whole-cell patch-clamp recording suggested that P2X4R also regulated AMPA receptor-mediated miniature excitatory postsynaptic currents and participated in the synaptic plasticity of spinal dorsal horn neurons. In summary, P2X4R was involved in AMPAR expression, electrophysiological function, and synaptic plasticity of spinal dorsal horn neurons through BDNF/TrkB signaling. This might be the mechanism underlying RIH, and hence inhibition of P2X4R might be a potential treatment strategy.
Learn More >Migraine, the third most common disease worldwide, is a well-known independent risk factor for subclinical focal deep white matter lesions (WML), even in young and otherwise individuals without cardiovascular risk factors. These white matter lesions are more commonly seen in migraine patients with transient neurological symptoms preceding their headaches, the so-called aura, and those with a high attack frequency. Despite their prevalence, the pathophysiology of migraine-related deep white matter hyperintensities remains poorly understood. Characteristic differences in their distribution when compared to common periventricular white matter lesions in the elderly that are related to chronic small vessel ischemic disease suggest a different underlying mechanism. Both ischemic and inflammatory mechanisms have been proposed, as there is increased cerebral vulnerability to ischemia in migraineurs, while there is also evidence for blood-brain-barrier disruption with associated release of pro-inflammatory substances during migraine attacks. An enhanced susceptibility to spreading depolarization, the electrophysiologic event underlying migraine, may be the underlying mechanism to cause repetitive episodes of cerebral hypoperfusion and neuroinflammation during migraine attacks. WML can negatively affect both physical and cognitive function, underscoring the public-health importance of migraine and suggesting that migraine is an important contributor to neurological deficits in the general population.
Learn More >The cytokine interleukin-31 has been implicated in the pathophysiology of multiple atopic disorderssuch asatopic dermatitis (AD), allergic rhinitisand airway hyperreactivity. In AD, IL-31 has been identified as one of the main 'drivers'of its cardinal symptom,pruritus. Here, we summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. T 2 cells play a central role in AD and release high levels ofT 2-associated cytokines including IL-31,thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch and neuronal outgrowth through activation ofthe heterodimeric receptor IL-31 receptor alpha (IL31RA)/Oncostatin M receptor (OSMRβ). IL31RA expression is found onhumanand murine dorsal root ganglia neurons, epithelial cells including keratinocytes as well asvarious innate immune cells. IL-31 is a critical cytokine involved in neuro-immune communication,which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31-downstream signalingmay be a beneficial approach for various inflammatory diseases including prurigo.However, as to whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory and pruritic disorders in the future.
Learn More >Symptomatic knee osteoarthritis (SKOA) is a chronic, disabling condition, requiring long-term pain management; over 800,000 SKOA patients in the USA use opioids chronically. We aim to characterize the societal economic burden of opioid use in this population.
Learn More >The clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed the key role of this axis in migraine pathogenesis. Three antibodies against CGRP – fremanezumab, galcanezumab and eptinezumab – and one antibody against the CGRP receptor, erenumab, are clinically approved therapeutics for the prevention of migraine. In addition, two small molecule CGRP receptor antagonists, ubrogepant and rimegepant, are approved for acute migraine treatment. Targeting either the CGRP ligand or receptor is efficacious for migraine treatment; however, a comparison of the mechanism of action of these therapeutic agents is lacking in the literature.
Learn More >Chronic pain commonly occurs in people living with HIV (PLWH). Many PLWH in the United States obtain opioids for chronic pain management. Whether insomnia severity and depressive symptoms are exacerbated by chronic pain and opioid use in PLWH remains to be determined. This study examined insomnia severity and depressive symptoms in 85 PLWH with chronic pain and 35 PLWH without chronic pain. Among PLWH with chronic pain, reported opioid use was examined in relation to insomnia severity and depressive symptoms. PLWH with chronic pain reported significantly greater insomnia severity ( = .033) and depressive symptoms ( = .025) than PLWH without chronic pain. Among PLWH with chronic pain who reported opioid use ( = 36), insomnia severity was greater compared to those who denied opioid use ( = 49), even after controlling for pain severity and number of comorbidities ( = .026). Greater pain severity was significantly associated with greater insomnia severity ( < .001) and depressive symptoms ( = .048) among PLWH with chronic pain who reported opioid use. These associations were not significant among those PLWH with chronic pain who denied opioid use. Findings suggest that PLWH with chronic pain are likely to experience poor sleep and depressed mood. Furthermore, poor sleep was associated with opioid use among PLWH with chronic pain.
Learn More >For decades, basic research on the underlying mechanisms of nociception has held promise to translate into efficacious treatments for patients with pain. Despite great improvement in the understanding of pain physiology and pathophysiology, translation to novel, effective treatments for acute and chronic pain has however been limited, and they remain an unmet medical need. In this opinion paper bringing together pain researchers from very different disciplines, the opportunities and challenges of translational pain research are discussed. The many factors that may prevent the successful translation of bench observations into useful and effective clinical applications are reviewed, including interspecies differences, limited validity of currently available preclinical disease models of pain, and limitations of currently used methods to assess nociception and pain in non-human and human models of pain. Many paths are explored to address these issues, including the backward translation of observations made in patients and human volunteers into new disease models that are more clinically relevant, improved generalization by taking into account age and sex differences, and the integration of psychobiology into translational pain research. Finally, it is argued that preclinical and clinical stages of developing new treatments for pain can be improved by better preclinical models of pathological pain conditions alongside revised methods to assess treatment-induced effects on nociception in human and non-human animals. Significance: For decades, basic research of the underlying mechanisms of nociception has held promise to translate into efficacious treatments for patients with pain. Despite great improvement in the understanding of pain physiology and pathophysiology, translation to novel, effective treatments for acute and chronic pain has however been limited, and they remain an unmet medical need.
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