Yoshizawa Kazumi, Arai Narumaki, Suzuki Yukina, Nakamura Toka, Takeuchi Kota, Sakamoto Reinii, Masuda Ritsuko
Laboratory of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan.
Department of Anesthesiology, Tokai University Hachioji Hospital, Tokyo, Japan.
Synapse. 2018 Jul 11. doi: 10.1002/syn.22056.
An important role of voltage-gated sodium channels (VGSCs) in many different pain states has been established in animal models and humans wherein sodium channel blockers partially ameliorate pain. However, behavioral tests for screening analgesics that exhibit pharmacologic action by acting on VGSCs are rarely reported, and there are no studies on antinociception using veratrine as a nociceptive agent. The aim of the present study was to examine the amount of nociceptive behavior evoked by subcutaneous administration of veratrine into the hind paw and investigate whether veratrine can be used as a VGSC agonist to test the pharmacological properties of candidate analgesics via sodium channel blockade. We report for the first time that intraplantar injection of veratrine produced a reproducible nociceptive response in mice. Furthermore, several sodium channel blockers, namely carbamazepine, valproate, mexiletine, and the selective Nav1.7 inhibitor PF-04856264, but not flecainide or pilsicainide, reduced veratrine-induced nociception. In contrast, calcium channel blockers gabapentin and ethosuximide did not change veratrine-induced nociception. The veratrine test in mice might be a useful tool, at least in part, to evaluate the potential analgesic effect of sodium channel blockers.
电压门控钠通道（VGSCs）在许多不同疼痛状态中的重要作用已在动物模型和人类中得到证实，其中钠通道阻滞剂可部分缓解疼痛。然而，通过作用于VGSCs发挥药理作用的镇痛药筛选行为学测试鲜有报道，且尚无使用藜芦碱作为伤害性刺激剂进行抗伤害感受的研究。本研究的目的是检测后爪皮下注射藜芦碱诱发的伤害性行为量，并研究藜芦碱是否可用作VGSC激动剂，通过钠通道阻滞来测试候选镇痛药的药理特性。我们首次报道足底注射藜芦碱可在小鼠中产生可重复的伤害性反应。此外，几种钠通道阻滞剂，即卡马西平、丙戊酸盐、美西律和选择性Nav1.7抑制剂PF-04856264，但氟卡尼或吡西卡尼则不然，可减轻藜芦碱诱发的伤害感受。相比之下，钙通道阻滞剂加巴喷丁和乙琥胺并未改变藜芦碱诱发的伤害感受。小鼠中的藜芦碱测试可能至少部分是评估钠通道阻滞剂潜在镇痛作用的有用工具。
