5-HT3 receptors and emesis

Nausea and vomiting. Nausea and vomiting is a major problem which occurs during and after the treatment with certain drugs like anesthetics, opioidanalgesics or cytostatics. Postoperative nausea and vomiting (PONV) is called the “big” little problem. As a consequence, the choice of the anesthetic drug(s) plays a role in preventing PONV [Apfel et al., Anesthesiology, 1999; Eberhart et al., Eur J Anaesthesiol, 1999]. Nausea and vomiting can be mediated via peripheral and/or central nervous pathways. Within the peripheral nervous system, vagal afferents, which are stimulated by 5-HT released from enterochromaffin cells, are of importance. The chemoreceptor trigger zone of the area postrema is another important center for the control of emesis. It is located at the boarder of the central nervous system and can be easily stimulated by drugs which do not enter the brain. In contrast, other centers which modulate emesis are located within the brain, e.g. the nucleus tractus solitarius. 5-HT3 receptors. In contrast to other neurotransmitter receptors which are involved in the modulation of emesis (including nicotinic ACh, dopamine2, histamine1, neurokinin, opioid, and cannabinoid receptors), 5-HT3 receptors are located in all emesiscontrolling centers mentioned above. It is known that 5-HT3 receptor antagonists successfully suppress nausea and vomiting [Tramer et al., Br Med J, 1997]. They can be used as antiemetics during therapy with cytostatics [Marty, Eur J Cancer, 1990] and are also useful against PONV [Rodrigo et al., Anaesth Intensive Care, 1994]. 5-HT3 receptors are ligand-gated ion channels which trigger fast postsynaptic transmission, like glycine-, nicotinic ACh and GABAA receptors. The 5-HT3A receptor is composed of five identical A-subunits which guarantee a constant stoichiometry. This is of advantage for the study of molecular mechanisms. In recent studies, the molecular mechanisms of (anti)emetic drugs at this receptor have been studied [Barann, et al., Naunyn Schmiedebergs Arch Pharmacol, 2000; Barann et al., Neuropharmacology, 2000; Barann et al., Br J Pharmacol, 2002; Walkembach et al., Br J Pharmacol, 2005; Barann et al., Eur J Pharamacol, 2006]. For this purpose, excised outside-out patches of HEK293 cells, stably transfected with the human 5-HT3A receptor cDNA were formed (voltage-clamp mode) and fast solution exchange systems were used. In addition, radioligand binding studies and [3H]5-HT uptake measurements (study of the 5-HT transporter) were performed supplementally. It was found that besides direct interactions of (anti)emetics with 5-HT3 receptors, the drugs may trigger indirect processes leading to changes of the free 5-HT concentration. Such mechanisms may include the changes in 5-HT metabolism, 5-HT uptake and 5-HT release. Results. As can be seen in Table 1, nearly all antiemetic drugs studied and some anesthetics with low emetogenic incidence, inhibited 5-HT3A receptors at clinical free plasma concentrations. The possible mechanisms underlying the inhibition are diverse and include allosteric modulatory sites [Barann et al., Br J Pharmacol, 2002], competitive antagonism [Walkembach et al., Br J Pharmacol, 2005], changes in desensitization kinetics, [Barann et al., Neuropharmacology, 2000] and block of the channel pore [Barann et al., Naunyn Schmiedebergs Arch Pharmacol, 2000; Schneider et al., in: Molecular and Basic Mechanisms of Anesthesia, Ed. Urban & Barann, 2002]. In contrast for most emetic drugs at clinical plasma concentrations, we found no inhibition. Some of these drugs induced weak potentiation (apomorphine [which showed intrinsic activity], ergotamine and morphine [which both slowed down desensitization]