Japundzić-Zigon N, Samardzić R, Beleslin D B
Department of Pharmacology, Faculty of Medicine, Belgrade, Yugoslavia.
Pharmacol Res. 1997 Apr;35(4):287-97. doi: 10.1006/phrs.1997.0133.
The emetic effect of clonidine injected into the cerebral ventricles through chronically implanted cannulae was investigated in unanaesthetized cats. Clonidine (0.1-300 micrograms) induced dose-dependent and shortlasting emesis. The emesis induced by the supramaximal dose of clonidine (100 micrograms) was not abolished after the ablation of area postrema. Both the alpha 2 adrenoceptor blocking agent idazoxan and the mixed alpha 1 and alpha 2 adrenoceptor antagonist phenoxybenzamine, injected intracerebroventricularly, attenuated or abolished the emesis induced by clonidine (100 micrograms). On the other hand, the alpha 2 adrenoceptor blocking agent yohimbine, the alpha 1 adrenoceptor blocking drug prazosin and the non-selective beta-adrenoceptor antagonist propranolol, injected into the cerebral ventricles, had no significant effect on clonidine-induced emesis. The antimuscarinic drug atropine injected into the cerebral ventricles prevented the clonidine-induced emesis in a dose-dependent manner. The dopamine antagonist chlorpromazine, the 5-hydroxytryptamine blocking agent methysergide and the histamine H1 and H2 receptor antagonists, antazoline and cimetidine, injected intracerebroventricularly reduced or abolished the emesis produced by clonidine. The ganglionic blocking substance mecamylamine and the opioid antagonist naloxone, all injected into the cerebral ventricles, had no significant effect on clonidine-induced emesis. In cats pretreated with the intracerebroventricular competitive inhibitor of the synthesis of catecholamines, alpha-methyl-p-tyrosine, as well as with the inhibitor of acetylcholine synthesis hemicholinium-3, the emesis caused by clonidine was depressed or abolished. The clonidine-induced emesis was also abolished when catecholamine stores were depleted by intracerebroventricular reserpine. However, the clonidine-induced emesis was not significantly changed when 5-hydroxylryptaminergic nerve terminals were damaged by 5,6-dihydroxytryptamine. It follows, therefore, that cholinergic and noradrenergic mechanisms are of basic importance for the emetic action of clonidine. With regard to receptors, the emesis induced by clonidine injected into the cerebral ventricles, is mediated at least in part through alpha-adrenoceptors, muscarinic cholinoceptors, 5-hydroxytryptamine receptors and H1 and H2 histamine receptors. These receptors appear to be located mostly presynaptically and they transmit emetic impulses to neurones integrating them into emesis. However, the direct effect of clonidine on postsynaptic receptors cannot be excluded, particularly when muscarinic and 5-hydroxytryptamine receptors are implicated. Taken together, these results point to the existence of a multitransmitter pathway/s outside the area postrema, subserving the central regulation of emesis.
通过长期植入的套管向未麻醉的猫脑室内注射可乐定的催吐作用进行了研究。可乐定（0.1 - 300微克）可引起剂量依赖性且持续时间短的呕吐。超最大剂量的可乐定（100微克）引起的呕吐在最后区切除后并未消除。脑室内注射α₂肾上腺素能受体阻断剂咪唑克生和α₁及α₂肾上腺素能受体混合拮抗剂酚苄明，可减弱或消除可乐定（100微克）引起的呕吐。另一方面，脑室内注射α₂肾上腺素能受体阻断剂育亨宾、α₁肾上腺素能受体阻断药哌唑嗪和非选择性β肾上腺素能受体拮抗剂普萘洛尔，对可乐定引起的呕吐无显著影响。脑室内注射抗胆碱能药物阿托品以剂量依赖性方式预防可乐定引起的呕吐。脑室内注射多巴胺拮抗剂氯丙嗪、5 - 羟色胺阻断剂麦角新碱以及组胺H₁和H₂受体拮抗剂安他唑啉和西咪替丁，可减少或消除可乐定引起的呕吐。脑室内注射神经节阻断物质美加明和阿片受体拮抗剂纳洛酮，对可乐定引起的呕吐无显著影响。在用脑室内注射儿茶酚胺合成的竞争性抑制剂α - 甲基 - p - 酪氨酸以及乙酰胆碱合成抑制剂半胱氨酸 - 3预处理的猫中，可乐定引起的呕吐受到抑制或消除。当通过脑室内注射利血平使儿茶酚胺储存耗竭时，可乐定引起的呕吐也被消除。然而，当5,6 - 二羟基色胺损伤5 - 羟色胺能神经末梢时，可乐定引起的呕吐没有明显变化。因此，可以得出结论，胆碱能和去甲肾上腺素能机制对可乐定的催吐作用至关重要。关于受体，脑室内注射可乐定引起的呕吐至少部分是通过α - 肾上腺素能受体、毒蕈碱胆碱能受体、5 - 羟色胺受体以及组胺H₁和H₂受体介导的。这些受体似乎大多位于突触前，它们将催吐冲动传递给神经元，将其整合为呕吐。然而，不能排除可乐定对突触后受体的直接作用，特别是当涉及毒蕈碱和5 - 羟色胺受体时。综上所述，这些结果表明在最后区之外存在一条多递质途径，参与呕吐的中枢调节。
