Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Neuroscience. 2012 Dec 27;227:336-49. doi: 10.1016/j.neuroscience.2012.09.079. Epub 2012 Oct 13.
Yokukansan (YKS) is a traditional Japanese medicine consisting of seven medicinal herbs that is used for the treatment of neurosis, insomnia, and the behavioral/psychological symptoms of dementia. This study examined the effects of YKS on morphine tolerance and physical dependence in mice. Daily oral administration of YKS (0.5 or 1.0 g/kg) for 3 weeks significantly attenuated morphine tolerance and naloxone-precipitated morphine withdrawal signs (jumps and body weight loss) without affecting the analgesic effect of morphine. The inhibitory effect of YKS on withdrawal jumps in morphine-dependent mice was blocked by a single pretreatment with an α(2)-adrenoceptor antagonist, yohimbine, but not by an α(1)-adrenoceptor antagonist, prazosin. A similar inhibitory effect on withdrawal jumps was observed by repeated administration of yohimbine. The membrane expression of α(2A)-adrenoceptors in the pons/medulla was decreased in morphine withdrawn animals; this reduction was prevented by repeated administration of YKS or yohimbine. Competitive radioligand and [(35)S]guanosine-5'-O-(3-thiotriphosphate) binding assays revealed that YKS and its constituent herbs, Glycyrrhiza (GR) and Uncaria hook (UH), had specific binding affinity for and antagonist activity against the α(2A)-adrenoceptor. Certain chemical constituents, including GR -derived glycyrrhizin and its metabolite, 18β-glycyrrhetinic acid, and UH-derived geissoschizine methyl ether (GME), shared such activities. Repeated administration of GR, UH, glycyrrhizin or GME significantly inhibited morphine withdrawal signs. These results suggest that YKS and its active constituents inhibit morphine tolerance and physical dependence, and that the latter is due at least in part to the prevention of the decreased membrane expression of the α(2A)-adrenoceptor in the brainstem by its prolonged blockade.
和汉三才汤（YKS）是一种由七种草药组成的传统日本药物，用于治疗神经症、失眠和痴呆的行为/心理症状。本研究探讨了 YKS 对吗啡耐受和躯体依赖的影响。连续 3 周每天口服 YKS（0.5 或 1.0 g/kg）可显著减轻吗啡耐受和纳洛酮诱发的吗啡戒断症状（跳跃和体重减轻），而不影响吗啡的镇痛作用。YKS 对吗啡依赖小鼠戒断跳跃的抑制作用被单次预先给予α2-肾上腺素受体拮抗剂育亨宾阻断，但不被 α1-肾上腺素受体拮抗剂哌唑嗪阻断。育亨宾重复给药也观察到对戒断跳跃的类似抑制作用。在吗啡戒断动物中，脑桥/延髓中的α2A-肾上腺素受体的膜表达减少；这种减少可被 YKS 或育亨宾的重复给药所预防。竞争性放射性配体和[35S]鸟苷-5'-O-（3-硫三磷酸）结合测定表明，YKS 及其组成草药甘草（GR）和钩藤（UH）对α2A-肾上腺素受体具有特异性结合亲和力和拮抗剂活性。某些化学成分，包括源自 GR 的甘草酸和其代谢物 18β-甘草次酸，以及源自 UH 的吉斯索嗪甲醚（GME），具有这种活性。GR、UH、甘草酸或 GME 的重复给药显著抑制吗啡戒断症状。这些结果表明，YKS 及其有效成分可抑制吗啡耐受和躯体依赖，后者至少部分是由于其长期阻断导致脑干部位的α2A-肾上腺素受体膜表达减少得到预防。
