Greco Maria Cristina, Navarra Pierluigi, Tringali Giuseppe
Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
Life Sci. 2016 Jan 15;145:161-5. doi: 10.1016/j.lfs.2015.12.032. Epub 2015 Dec 17.
In this study we tested the hypothesis that tapentadol inhibits GGRP release from the rat brainstem through a mechanism mediated by the inhibition of NA reuptake; as a second alternative hypothesis, we investigated whether tapentadol inhibits GGRP release via the inhibition of 5-HT reuptake.
Rat brainstems were explanted and incubated in short-term experiments. CGRP released in the incubation medium was taken as a marker of CGRP release from the central terminals of trigeminal neurons within the brainstem. CGRP levels were measured by radioimmunoassay under basal conditions or in the presence of tapentadol; NA, 5-HT, clonidine, yohimbine and ondansetron were used as pharmacological tools to investigate the action mechanism of tapentadol.
The α2-antagonist yohimbine failed to counteract the effects of tapentadol. Moreover, neither NA nor the α2-agonist clonidine per se inhibited K(+)-stimulated CGRP release, thereby indicating that the effects of tapentadol are nor mediated through the block of NA reuptake. Further experiments showed that 5-HT and tramadol, which inhibits both NA and 5-HT reuptake, significantly reduced K(+)-stimulated CGRP release. Moreover, the 5-HT3 antagonist ondansetron was able to counteract the effects of tapentadol in this system.
This study provided pharmacological evidence that tapentadol inhibits stimulated CGRP release from the rat brainstem in vitro through a mechanism involving an increase in 5-HT levels in the system and the subsequent activation of 5-HT3 receptors.
在本研究中，我们检验了以下假设：曲马多通过抑制去甲肾上腺素（NA）再摄取介导的机制抑制大鼠脑干中胃动素释放肽（GGRP）的释放；作为第二个替代假设，我们研究了曲马多是否通过抑制5-羟色胺（5-HT）再摄取来抑制GGRP释放。
取出大鼠脑干并进行短期实验培养。将培养介质中释放的降钙素基因相关肽（CGRP）作为脑干内三叉神经元中枢终末释放CGRP的标志物。在基础条件下或存在曲马多的情况下，通过放射免疫分析法测量CGRP水平；使用NA、5-HT、可乐定、育亨宾和昂丹司琼作为药理学工具来研究曲马多的作用机制。
α2拮抗剂育亨宾未能抵消曲马多的作用。此外，NA和α2激动剂可乐定本身均未抑制钾离子（K(+)）刺激的CGRP释放，从而表明曲马多的作用不是通过阻断NA再摄取介导的。进一步的实验表明，5-HT和抑制NA和5-HT再摄取的曲马朵显著降低了K(+)刺激的CGRP释放。此外，5-HT3拮抗剂昂丹司琼能够抵消曲马多在该系统中的作用。
本研究提供了药理学证据，表明曲马多在体外通过一种涉及系统中5-HT水平升高及随后5-HT3受体激活的机制抑制大鼠脑干中刺激后的CGRP释放。
