CLONIDINE-INDUCED EMESIS: A MULTITRANSMITTER PATHWAY CONCEPT

Abstract

The emetic effect of clonidine injected into the cerebral ventricles through chronically implanted cannulae was investigated in unanaesthetized cats. Clonidine (0.1–300gmg) induced dose-dependent and shortlasting emesis. The emesis induced by the supramaximal dose of clonidine (100gmg) was not abolished after the ablation of area postrema. Both the α2adrenoceptor blocking agent idazoxan and the mixedα1andα2adrenoceptor antagonist phenoxybenzamine, injected intracerebroventricularly, attenuated or abolished the emesis induced by clonidine (100gmg). On the other hand, the α2adrenoceptor blocking agent yohimbine, theα1adrenoceptor blocking drug prazosin and the non-selectiveβ-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 H1and H2receptor 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,α-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-hydroxytryptaminergic 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 throughα-adrenoceptors, muscarinic cholinoceptors, 5-hydroxytryptamine receptors and H1and H2histamine 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.