Department of Basic Medical Sciences, College of Osteopathic Medicine of Pacific, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766, USA.
Pharmacol Biochem Behav. 2011 Oct;99(4):573-9. doi: 10.1016/j.pbb.2011.05.025. Epub 2011 Jun 13.
Significant electrophysiological and biochemical findings suggest that receptor cross-talk occurs between serotonergic 5-HT(3)- and tachykininergic NK(1)-receptors in which co-activation of either receptor by ineffective doses of their corresponding agonists (serotonin (5-HT) or substance P (SP), respectively) potentiates the activity of the other receptor to produce a response. In contrast, selective blockade of any one of these receptors attenuates the increase in abdominal vagal afferent activity caused by either 5-HT or SP. This interaction has important implications in chemotherapy-induced nausea and vomiting (CINV) since 5-HT(3)- and NK(1)-receptor antagonists are the major classes of antiemetics used in cancer patients receiving chemotherapy. The purpose of this study was to demonstrate whether the discussed interaction produces effects at the behavioral level in a vomit-competent species, the least shrew. Our results demonstrate that pretreatment with either a 5-HT(3) (tropisetron)- or an NK(1) (CP99,994)-receptor specific antagonist, attenuates vomiting caused by a selective agonist (2-methyl 5-HT or GR73632, respectively) of both emetic receptors. In addition, relative to each antagonist alone, their combined doses were 4-20 times more potent against vomiting caused by each emetogen. Moreover, combined sub-maximal doses of the agonists 2-methyl 5-HT and GR73632, produced 8-12 times greater number of vomits relative to each emetogen tested alone. However, due to large variability in vomiting caused by the combination doses, the differences failed to attain significance. The antiemetic dose-response curves of tropisetron against both emetogens were U-shaped probably because larger doses of this antagonist behave as a partial agonist. The data demonstrate that 5-HT(3)- and NK(1)-receptors cross-talk to produce vomiting, and that synergistic antiemetic effects occur when both corresponding antagonists are concurrently used against emesis caused by each specific emetogen.
显著的电生理学和生物化学发现表明，5-羟色胺能 5-HT(3)-和速激肽能 NK(1)-受体之间存在受体串扰，其中两种受体分别被其相应激动剂（5-羟色胺（5-HT）或 P 物质（SP））的无效剂量共同激活，增强了另一种受体的活性，从而产生反应。相反，选择性阻断这些受体中的任何一种都会减弱 5-HT 或 SP 引起的腹部迷走传入活动的增加。这种相互作用在化疗引起的恶心和呕吐（CINV）中具有重要意义，因为 5-HT(3)-和 NK(1)-受体拮抗剂是癌症患者接受化疗时使用的主要抗恶心药物类别。本研究的目的是证明在一种具有呕吐能力的物种（least shrew）中，这种讨论的相互作用是否会在行为水平上产生影响。我们的结果表明，预先用 5-HT(3)（tropisetron）或 NK(1)（CP99,994）受体特异性拮抗剂处理，可减轻两种呕吐受体的选择性激动剂（2-甲基 5-HT 或 GR73632）引起的呕吐。此外，与每种拮抗剂单独使用相比，它们的组合剂量对每种致吐原引起的呕吐的效力提高了 4-20 倍。此外，2-甲基 5-HT 和 GR73632 的组合亚最大剂量产生的呕吐次数比单独测试的每种致吐原分别增加了 8-12 倍。然而，由于组合剂量引起的呕吐变异性较大，差异未能达到显著水平。tropisetron 对两种致吐原的抗呕吐剂量-反应曲线呈 U 形，可能是因为这种拮抗剂的较大剂量表现为部分激动剂。数据表明，5-HT(3)-和 NK(1)-受体串扰产生呕吐，并且当两种相应的拮抗剂同时用于对抗每种特定致吐原引起的呕吐时，会产生协同的抗恶心作用。
