Harada Yumi, Iizuka Seiichi, Saegusa Yayoi, Mogami Sachiko, Fujitsuka Naoki, Hattori Tomohisa
Tsumura Kampo Research Laboratories, Tsumura & Co., Ibaraki, Japan (Y.H., S.I., Y.S., S.M., N.F., T.H.).
Tsumura Kampo Research Laboratories, Tsumura & Co., Ibaraki, Japan (Y.H., S.I., Y.S., S.M., N.F., T.H.)
J Pharmacol Exp Ther. 2017 Jul;362(1):78-84. doi: 10.1124/jpet.117.240630. Epub 2017 May 2.
Opioid receptor stimulants are analgesics used in patients with and without cancer; however, they often cause constipation, resulting in poor adherence and deterioration of the quality of life. Hence, suitable treatments for constipation are required. In this study, we investigated the pharmacological mechanisms of action of mashiningan (MNG), a Kampo medicine used to treat constipation, and evaluated the effect of MNG on opioid-induced constipation in rats. MNG (100 or 300 mg/kg) was orally administered to normal or codeine phosphate (CPH)-induced constipation in rats, and its effect was evaluated on the basis of fecal counts, characteristics, and weight. Small intestinal fluid secretion was measured after treatment with MNG alone or coadministration with a cystic fibrosis transmembrane conductance regulator (CFTR)-specific inhibitor (CFTRinh-172). The effects of MNG on the CFTR and type-2 chloride channel were determined using patch-clamp or short-circuit current experiments, respectively. MNG increased the fecal weight and proportion of soft feces in normal rats. CPH-induced constipation in rats decreased fecal counts and weight, whereas MNG prevented these effects and increased the proportion of soft feces. MNG increased the electronic chloride current, and this effect was inhibited by the CFTRinh-172 in the CFTR assay. Furthermore, MNG increased small intestinal fluid secretion, and this effect was abolished by coadministration with the CFTRinh-172. MNG improved opioid-induced constipation in rats, and this improvement may have been mediated by increasing intestinal fluid secretion via CFTR chloride channel activation. Therefore, MNG is expected as a medicine of the treatment of constipation in patients taking opioids.
阿片受体激动剂是用于患有或未患有癌症患者的镇痛药；然而，它们常常导致便秘，从而致使依从性差和生活质量下降。因此，需要合适的便秘治疗方法。在本研究中，我们调查了用于治疗便秘的汉方药麻子仁丸（MNG）的药理作用机制，并评估了MNG对大鼠阿片类药物引起的便秘的影响。将MNG（100或300mg/kg）口服给予正常大鼠或磷酸可待因（CPH）诱导便秘的大鼠，并根据粪便计数、特征和重量评估其效果。单独给予MNG或与囊性纤维化跨膜传导调节因子（CFTR）特异性抑制剂（CFTRinh-172）共同给药后，测量小肠液分泌。分别使用膜片钳或短路电流实验确定MNG对CFTR和2型氯离子通道的影响。MNG增加了正常大鼠的粪便重量和软便比例。CPH诱导的大鼠便秘减少了粪便计数和重量，而MNG可预防这些影响并增加软便比例。MNG增加了氯离子电流，并且在CFTR测定中这种作用被CFTRinh-172抑制。此外，MNG增加了小肠液分泌，并且与CFTRinh-172共同给药可消除这种作用。MNG改善了大鼠阿片类药物引起的便秘，这种改善可能是通过激活CFTR氯离子通道增加肠液分泌介导的。因此，MNG有望成为治疗服用阿片类药物患者便秘的药物。
