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• W3120795854 abstract "Gabapentinoids such as gabapentin and pregabalin, which bind specifically to the α2δ subunit of voltage-gated Ca2+ channels, are used for first-line treatment of neuropathic pain. Here, we examined the analgesic effect of mirogabalin besilate (referred to simply as mirogabalin), a novel gabapentinoid, focusing on its action on the spinal cord and the descending noradrenergic pain inhibitory system. When administered systemically (10 and 30 mg/kg, intraperitoneally (i.p.)) and locally (10 and 30 μg, intracerebroventricularly (i.c.v.) or intrathecally (i.t.)) to mice, mirogabalin was found to exert analgesic effects on thermal (plantar test) and mechanical (von Frey test) hypersensitivity developing after partial sciatic nerve ligation. Notably, its analgesic effects (30 mg/kg, i.p. and 30 μg, i.c.v.) disappeared in mice pretreated with yohimbine hydrochloride (3 μg, i.t.). Moreover, in mice harboring a mutation in the α2δ-1 subunit resulting in substitution of arginine at position 217 with alanine to prevent gabapentinoid binding (R217A mutant mice), the analgesic effects of pregabalin and mirogabalin (30 μg, i.c.v., respectively) on mechanical hypersensitivity were almost completely suppressed. These results clearly demonstrate that mirogabalin also operates via the descending noradrenergic system, and that binding to the α2δ-1 subunit supraspinally is essential for the pain relief effect of gabapentinoids." @default.
• W3120795854 created "2021-01-18" @default.
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• W3120795854 date "2021-05-01" @default.
• W3120795854 modified "2023-10-14" @default.
• W3120795854 title "Mirogabalin activates the descending noradrenergic system by binding to the α2δ-1 subunit of voltage-gated Ca2+ channels to generate analgesic effects" @default.
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• W3120795854 doi "https://doi.org/10.1016/j.jphs.2021.01.002" @default.
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