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Jararhagin is a hyperalgesic metalloproteinase from Bothrops jararaca venom. In rodents, jararhagin induces nociceptive behaviors that correlate with an increase in peripheral cytokine levels. However, the role of the spinal cord glia in pain processing after peripheral stimulus of jararhagin has not been investigated. Aiming to explore this proposal, mice received intraplantar (i.pl.) injection of jararhagin and the following parameters were evaluated: hyperalgesia, spinal cord TNF-α, IL-1β levels, and CXCR1, GFAP and p-NFκB activation. The effects of intrathecal (i.t.) injection of TNF-α soluble receptor (etanercept), IL-1 receptor antagonist (IL-1Ra), and inhibitors of NFκB (PDTC), microglia (minocycline) and astrocytes (α-aminoadipate) were investigated. Jararhagin inoculation induced cytokine production (TNF-α and IL-1β) in the spinal cord, which was reduced by treatment with PDTC (40% and 50%, respectively). Jararhagin mechanical hyperalgesia and cytokine production were inhibited by treatment with etanercept (67%), IL-1Ra (60%), PDTC (70%), minocycline (60%) and α-aminoadipate (45%). Furthermore, jararhagin induced an increase in p-NFκB, CXCR1 and GFAP detection in the spinal cord indicating activation of NFκB, microglia and astrocytes. These results demonstrate for the first time that jararhagin-induced mechanical hyperalgesia is dependent on spinal cord activation of glial cells, consequent NFκB activation, and cytokine production in mice.
Learn More >Although conventional pain relief therapeutics have centered around mu-opioid agonists, these drugs are limited by adverse side effects, including respiratory depression and addiction potential. The ongoing opioid epidemic has galvanized research into novel analgesic therapies with more favorable profiles. New pharmacologic agents have been developed to target neuronal pathways involved in pain sensation. Certain receptors have been recognized to mediate nociceptive transmission, central sensitization, and the development of chronic pain states.
Learn More >Effective control of pain management has the potential to significantly decrease the need for prescription opioids following a surgical procedure. While extended release products for pain management are available commercially, the implementation of a device that safely and reliably provides extended analgesia and is sufficiently flexible to facilitate a diverse array of release profiles would serve to advance patient comfort, quality of care and compliance following surgical procedures. Herein, we review current polymeric systems that could be utilized in new, controlled post-operative pain management devices and highlight where opportunities for improvement exist.
Learn More >Calcitonin gene-related peptide (CGRP) is a vasodilatory neuropeptide that plays an essential role in the pathophysiology of migraine, a highly disabling neurovascular disorder characterized by severe headache attacks. Rimegepant is a small-molecule CGRP receptor antagonist that is approved by the FDA for the acute treatment of migraine and currently under investigation for migraine prophylaxis.
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 >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 >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 >Cancer diagnosis and treatment are drastic events for patients and their families. Besides psychological aspects of the disease, patients are often affected by severe side effects related to the cancer itself or as a result of therapeutic interventions. Particularly, chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of oral or intravenous chemotherapy. The disorder may require dose reduction of chemotherapy and is accompanied by multiple symptoms with long-term functional impairment affecting quality of life (QoL), e.g., sensory and functional deteriorations as well as severe pain. Although CIPN may reverse or improve after termination of the causative chemotherapy, approximately 30-40% of patients are faced with chronicity of the symptoms. Due to the advantages in cancer diagnosis and treatments, survival rates of cancer patients rise and CIPN may occur even more frequently in the future. In this review, we summarize current recommendations of leading national and international societies regarding prevention and treatment options in CIPN. A special focus will be placed on current evidence for topical treatment of CIPN with high-dose capsaicin. Finally, an algorithm for CIPN treatment in clinical practice is provided, including both pharmacologic and non-pharmacologic modalities based on the clinical presentation.
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