The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes
The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes
复制标题
DOI：
10.1159/000093179
复制
发表时间：
2006-01-01
期刊：
影响因子：
3.1
通讯作者：
Shigematsu, Akio
中科院分区：
文献类型：
--
作者：
Horishita, Takafumi;Minami, Kouichiro;Shigematsu, Akio
目的：曲马多作为一种止痛药被广泛应用于临床，但其产生抗伤害性作用的机制尚不清楚。曲马多的主要代谢物O-去甲基曲马多是一种比曲马多更有效的止痛药。我们以前曾报道，曲马多抑制5-羟色胺(5-HT)2C型受体(5-HT2CR)，5-HT2CR是一种G蛋白偶联受体，广泛表达于大脑中，介导5-HT的几种作用，包括伤害性感受、摄食和运动。O-去甲基曲马多对5-HT2CR的影响尚未见报道。在本研究中，我们研究了O-去甲基曲马多对非洲爪哇卵母细胞表达5-HT2CR的影响。方法：利用非洲爪哇卵母细胞表达系统检测O-去甲基曲马多对5-HT2CR的影响。此外，我们还考察了O-脱甲基曲马多对5-HT2CR与[H-3]5-HT结合的影响。结果：O-去甲基曲马多在药物相关浓度下可抑制表达5-HT2CR的卵母细胞上由5-羟色胺引起的钙激活氯离子电流。O-去甲基曲马多对5-HT2CR的抑制作用在较高浓度的5-羟色胺时被克服。蛋白激酶C抑制剂双吲哚马来酰亚胺I(GF109203X)可增加5-羟色胺诱发电流，但对O-去甲基曲马多抑制5-羟色胺诱发电流的作用不明显。O-去甲基曲马多抑制卵母细胞表达的5-HT2CR与[H-3]5-羟色胺的特异性结合。O-去甲基曲马多改变了5-HT2CR与[H-3]5-羟色胺结合的表观解离常数，但不改变最大结合量，这表明竞争抑制。结论：O-去甲基曲马多对5-羟色胺(2C)受体有抑制作用，为进一步研究曲马多和O-去甲基曲马多的药理作用提供了依据。版权所有(C)2006 S.Karger AG，巴塞尔。
Purpose: Tramadol is widely used clinically as an analgesic, yet the mechanism by which it produces antinociception remains unclear. O-Desmethyl tramadol, the main metabolite of tramadol, is a more potent analgesic than tramadol. We reported previously that tramadol inhibits the 5-hydroxytryptamine (5-HT) type 2C receptor (5-HT2CR), a G-protein-coupled receptor that is expressed widely within brain and that mediates several effects of 5-HT, including nociception, feeding, and locomotion. The effects of O-desmethyl tramadol on 5-HT2CR have not been studied. In this study, we investigated the effect of O-desmethyl tramadol on 5-HT2CR expressed in Xenopus oocytes. Methods:We examined the effect of O-desmethyl tramadol on 5-HT2CR using the Xenopus oocyte expression system. Furthermore, we investigated the effects of O-desmethyl tramadol on the binding of [H-3]5-HT by 5-HT2CR. Results: O-Desmethyl tramadol, at pharmacologically relevant concentrations, inhibited 5-HT-evoked Ca2+-activated Cl- currents in oocytes that expressed 5-HT2CR. The inhibitory effect of O-desmethyl tramadol on 5-HT2CR was overcome at higher concentrations of 5-HT. Bisindolylmaleimide I (GF109203X), a protein kinase C inhibitor, increased 5-HT-evoked currents but had little effect on the inhibition of 5-HT-evoked currents by O-desmethyl tramadol. O-Desmethyl tramadol inhibited the specific binding of [H-3]5-HT by 5-HT2CR expressed in oocytes. O-Desmethyl tramadol altered the apparent dissociation constant for binding of [H-3]5-HT by 5-HT2CR without changing maximum binding, which indicated competitive inhibition. Conclusion: These results suggest that O-desmethyl tramadol inhibits 5HT(2C)R, which provides further insight into the pharmacological properties of tramadol and O-desmethyl tramadol. Copyright (c) 2006 S. Karger AG, Basel.