Details

Autor(en) / Beteiligte

• Watanabe, Shun
• Iwai, Takashi
• Tanabe, Mitsuo
• Oyama, Misa

Titel

Mirogabalin activates the descending noradrenergic system by binding to the [alpha].sub.2[delta]-1 subunit of voltage-gated Ca.sup.2+ channels to generate analgesic effects

Ist Teil von

• Journal of pharmacological sciences, 2021-05, Vol.146 (1), p.33

Ort / Verlag

Elsevier B.V

Erscheinungsjahr

2021

Link zum Volltext

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• Keywords Mirogabalin; Gabapentinoid; Neuropathic pain; [alpha].sub.2[delta]-1 subunit; Descending noradrenergic pain inhibitory system Gabapentinoids such as gabapentin and pregabalin, which bind specifically to the [alpha].sub.2[delta] subunit of voltage-gated Ca.sup.2+ 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 [mu]g, 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 [mu]g, i.c.v.) disappeared in mice pretreated with yohimbine hydrochloride (3 [mu]g, i.t.). Moreover, in mice harboring a mutation in the [alpha].sub.2[delta]-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 [mu]g, 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 [alpha].sub.2[delta]-1 subunit supraspinally is essential for the pain relief effect of gabapentinoids. Author Affiliation: (a) Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan (b) Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan * Corresponding author. Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Fax: +81 3 3442 3875. Article History: Received 7 December 2020; Revised 28 December 2020; Accepted 5 January 2021 (footnote) Peer review under responsibility of Japanese Pharmacological Society. Byline: Misa Oyama (a,b), Shun Watanabe (a,b), Takashi Iwai (a,b), Mitsuo Tanabe [tanabemi@pharm.kitasato-u.ac.jp] (a,b,*)