Oyama Misa, Watanabe Shun, Iwai Takashi, Tanabe Mitsuo
Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
J Pharmacol Sci. 2021 May;146(1):33-39. doi: 10.1016/j.jphs.2021.01.002. Epub 2021 Jan 7.
Gabapentinoids such as gabapentin and pregabalin, which bind specifically to the αδ subunit of voltage-gated Ca 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 αδ-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 αδ-1 subunit supraspinally is essential for the pain relief effect of gabapentinoids.
加巴喷丁类药物，如加巴喷丁和普瑞巴林，可特异性结合电压门控钙通道的αδ亚基，用于神经性疼痛的一线治疗。在此，我们研究了新型加巴喷丁类药物甲磺酸米罗加巴林（简称为米罗加巴林）的镇痛作用，重点关注其对脊髓和下行去甲肾上腺素能疼痛抑制系统的作用。当对小鼠进行全身给药（10和30mg/kg，腹腔注射（i.p.））和局部给药（10和30μg，脑室内（i.c.v.）或鞘内（i.t.））时，发现米罗加巴林对坐骨神经部分结扎后出现的热（足底试验）和机械（von Frey试验）超敏反应具有镇痛作用。值得注意的是，在用盐酸育亨宾（3μg，i.t.）预处理的小鼠中，其镇痛作用（30mg/kg，i.p.和30μg，i.c.v.）消失。此外，在αδ-1亚基发生突变导致第217位精氨酸被丙氨酸取代以阻止加巴喷丁类药物结合的小鼠（R217A突变小鼠）中，普瑞巴林和米罗加巴林（分别为30μg，i.c.v.）对机械超敏反应的镇痛作用几乎完全被抑制。这些结果清楚地表明，米罗加巴林也通过下行去甲肾上腺素能系统发挥作用，并且在脊髓上与αδ-1亚基结合对于加巴喷丁类药物的疼痛缓解作用至关重要。
