Pain
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Platinum-based anticancer drugs cause neurotoxicity. In particular, oxaliplatin produces early-developing, painful, and cold-exacerbated paresthesias. However, the mechanism underlying these bothersome and dose-limiting adverse effects is unknown. ⋯ Administration of cisplatin evoked mechanical allodynia, an effect that was reduced in TRPA1-deficient mice. TRPA1 is therefore required for oxaliplatin-evoked mechanical and cold hypersensitivity, and contributes to cisplatin-evoked mechanical allodynia. Channel activation is most likely caused by glutathione-sensitive molecules, including reactive oxygen species and their byproducts, which are generated after tissue exposure to platinum-based drugs from cells surrounding nociceptive nerve terminals.
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The neuropeptide bradykinin (BK) sensitizes nociceptor activation following its release in response to inflammatory injury. Thereafter, the bioactivity of bradykinin is controlled by the enzymatic activities of circulating peptidases. One such enzyme, the metalloendopeptidase EC3.4.24.15 (EP24.15), is co-expressed with bradykinin receptors in primary afferent neurons. ⋯ In addition, bradykinin-induced sensitization of TRPV1 activation was increased in the presence of the EP24.15/16 inhibitor JA-2. Furthermore, behavioral analyses illustrated a significant dose-response relationship between JA-2 and bradykinin-mediated thermal hyperalgesia. These results indicate an important physiological role for the metallopeptidases EP24.15 and EP24.16 in regulating bradykinin-mediated sensitization of primary afferent nociceptors.
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Randomized Controlled Trial
GDNF levels in the lower lip skin in a rat model of trigeminal neuropathic pain: implications for nonpeptidergic fiber reinnervation and parasympathetic sprouting.
Trigeminal neuropathic pain is associated with trigeminal nerve damage. Significant remodeling of the peripheral nervous system may contribute to the pain; however, the changes and the factors that drive them have not been well described. In this study, a partial injury of the mental nerve of the rat, a purely sensory branch of the trigeminal nerve, resulted in prolonged mechanical allodynia in the lower lip skin persisting up to 4 months. ⋯ Meanwhile, the glial cell line-derived growth factor (GDNF) showed a quick upregulation in the skin after nerve lesioning, with levels peaking at 4 weeks. This suggests that an excess of GDNF in the skin drives the nonpeptidergic C-fiber regeneration and parasympathetic fiber sprouting in the upper dermis, and could be an important mechanism in trigeminal neuropathic pain. This article provides an in-depth description of the changes in nonpeptidergic fibers in the skin after nerve lesioning, and measures, for the first time, GDNF protein levels in the skin after a nerve lesion, providing strong evidence for the role of GDNF in modulating innervation of the nonpeptidergic and parasympathetic fibers in the skin after injury.
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Transient receptor potential ion channel melastatin subtype 8 (TRPM8) is activated by cold temperatures and cooling agents, such as menthol and icilin. Compounds containing peppermint are reported to reduce symptoms of bowel hypersensitivity; however, the underlying mechanisms of action are unclear. Here we determined the role of TRPM8 in colonic sensory pathways. ⋯ Icilin also prevented mechanosensory desensitization and sensitization induced by capsaicin and the TRPA1 agonist AITC (40 μmol/L), respectively. TRPM8 is present on a select population of colonic high threshold sensory neurons, which may also co-express TRPV1. TRPM8 couples to TRPV1 and TRPA1 to inhibit their downstream chemosensory and mechanosensory actions.