PR2'2006.Vp:Corelventura

Modulation of chemical signalling: Current problems after four decades of research Symposium 5-HT3 receptors and emesis Martin Barann1,2, Michael Bruess2, Marion Brinkmann1, Isabelle Linden1, Mina Lyutenska1, Marc Schneider1, Jan Walkembach1, Maria Wittmann1 Clinics of Anaesthesiology and Operative Intensive Care, University of Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany; Institute of Pharmacology and Toxicology, University of Bonn, Reuterstr. 2b, D-53113 Bonn, Germany; e-mail: [email protected] Nausea and vomiting. Nausea and vomiting is a ma- mechanisms. In recent studies, the molecular mecha- jor problem which occurs during and after the treat- nisms of (anti)emetic drugs at this receptor have been ment with certain drugs like anesthetics, opioid- studied [Barann, et al., Naunyn Schmiedebergs Arch analgesics or cytostatics. Postoperative nausea and Pharmacol, 2000; Barann et al., Neuropharmacology, vomiting (PONV) is called the “big” little problem. 2000; Barann et al., Br J Pharmacol, 2002; Walkem- As a consequence, the choice of the anesthetic drug(s) bach et al., Br J Pharmacol, 2005; Barann et al., Eur J plays a role in preventing PONV [Apfel et al., Anes- Pharamacol, 2006]. For this purpose, excised thesiology, 1999; Eberhart et al., Eur J Anaesthesiol, outside-out patches of HEK293 cells, stably trans- via 1999]. Nausea and vomiting can be mediated pe- fected with the human 5-HT3A receptor cDNA were ripheral and/or central nervous pathways. Within the formed (voltage-clamp mode) and fast solution exchange peripheral nervous system, vagal afferents, which are systems were used. In addition, radioligand binding stud- stimulated by 5-HT released from enterochromaffin ies and [3H]5-HT uptake measurements (study of the cells, are of importance. The chemoreceptor trigger 5-HT transporter) were performed supplementally. It was zone of the area postrema is another important center found that besides direct interactions of (anti)emetics with for the control of emesis. It is located at the boarder of 5-HT3 receptors, the drugs may trigger indirect processes the central nervous system and can be easily stimu- leading to changes of the free 5-HT concentration. Such lated by drugs which do not enter the brain. In con- mechanisms may include the changes in 5-HT metabo- trast, other centers which modulate emesis are located lism, 5-HT uptake and 5-HT release. within the brain, e.g. the nucleus tractus solitarius. Results. As can be seen in Table 1, nearly all antiemetic 5-HT3 receptors. In contrast to other neurotrans- drugs studied and some anesthetics with low mitter receptors which are involved in the modulation emetogenic incidence, inhibited 5-HT3A receptors at of emesis (including nicotinic ACh, dopamine2, hista- clinical free plasma concentrations. The possible mine1, neurokinin, opioid, and cannabinoid recep- mechanisms underlying the inhibition are diverse and tors), 5-HT3 receptors are located in all emesis- include allosteric modulatory sites [Barann et al., Br controlling centers mentioned above. It is known that J Pharmacol, 2002], competitive antagonism [Walkem- 5-HT3 receptor antagonists successfully suppress nau- bach et al., Br J Pharmacol, 2005], changes in desen- sea and vomiting [Tramer et al., Br Med J, 1997]. sitization kinetics, [Barann et al., Neuropharmacol- They can be used as antiemetics during therapy with ogy, 2000] and block of the channel pore [Barann et cytostatics [Marty, Eur J Cancer, 1990] and are also al., Naunyn Schmiedebergs Arch Pharmacol, 2000; useful against PONV [Rodrigo et al., Anaesth Inten- Schneider et al., in: Molecular and Basic Mechanisms sive Care, 1994]. 5-HT3 receptors are ligand-gated of Anesthesia, Ed. Urban & Barann, 2002]. ion channels which trigger fast postsynaptic transmis- In contrast for most emetic drugs at clinical plasma sion, like glycine-, nicotinic ACh and GABAA recep- concentrations, we found no inhibition. Some of these tors. The 5-HT3A receptor is composed of five identi- drugs induced weak potentiation (apomorphine cal A-subunits which guarantee a constant stoichio- [which showed intrinsic activity], ergotamine and metry. This is of advantage for the study of molecular morphine [which both slowed down desensitization] Pharmacological Reports, 2006, 58, 253272 253 sides its low affinity for µ-opioid receptors, inhibits the reuptake transporters for norepinephrine and 5-HT. It was found that tramadol, but not its active metabolite O-demethyltramadol, suppressed the human 5-HT transporter by 80% at plasma concentrations which are obtained after rapid titration (Fig. 1.). At this concentration range, the human 5-HT3A receptor was practically unaffected by tramadol (inhibition less than 6%) [Barann et al., Eur J Pharamacol, 2006]. As a consequence, it is possible that the 5-HT re- Fig. 1. Effects of (±) tramadol on the human 5-HT transporter 3A ! ([ H]5-HT uptake) and the human 5HT!) receptor (patch clamp). The ceptor is still sensitive against any raise of 5-HT lev- data are presented as the means of 35 experiments ± SD els induced by this drug. The same indirect mechanism appears not to be valid for morphine, since re- and halothane [which accelerated the activation]; (un- cent unpublished experiments suggest that this opioid published data). does not inhibit the 5-HT transporter. indirect An mechanism at 5-HT3 receptors might Applying fast solution exchange systems on the ex- be valid for tramadol, an atypical analgesic which, be- cised patches, it is possible to record processes with Tab. 1. Effects (A, M, P, D) of (anti) emetics at human 5-HT!) receptors Drug Plasma concentration (µM) IC# (µM) Effect (A–D) Inhibition in plasma (%) anti-emetics: Cannabinoids (7) 0.02–0.2 0.03–0.3 M 10–50 Ondansetron 0.2 0.0003 AC 100 Metoclopramide 0.1–0.2 0.060 AC 75 Propofol 1 14 P, D (?) < 15 Tropisetron 0.2 0.0003 AC 100 emetics: Apomorphine 0.0001 0.4 AA, D 0 + partial Agonist* Ergotamine 0.001 > 30 D 0* Halothane 200 n.d. AA (?) 0* Tramadol 7 200 (indirect, transporter 5** inhib.) Morphine 0.15 0.3 AC, M (?) 0–30* O-Demethyltramadol 1.0 100 – 0 „neutral“ drugs (low incidence of emesis): Methohexital 1.1 125 P 0 Pentobarbital 78 120 P 30 Sevofluran 300 430 P 30 Thiopental 9 78 P < 10 The data suggest that emetogenic drugs, in contrast to antiemetic drugs, produce no inhibition of human 5-HT!) receptors at clinical (free) plasma concentrations. Some emetic drugs (apomorphine, halothane, ergotamine, morphine, unpublished data) resulted in potentiation (*) and the emetic analgesic tramadol may activate 5-HT! receptors indirectly via a 5-HT transporter inhibition (**). Possible mechanisms: AA, AC = agonist binding site (activation or competitive antagonism), M = allosteric, modulatory binding site (e.g. cannabinoids), P = channel pore, D = desensitization 254 Pharmacological Reports, 2006, 58, 253272 Modulation of chemical signalling: Current problems after four decades of research Symposium time constants well below 10 ms (e.g. receptor activa- (1) Clinical plasma concentrations of antiemetics and tion or channel block). The measured signals (peak low-emetogenic anesthetics inhibit human 5-HT3A re- currents) might then occur within 20 ms. However, ceptors. taking these peak currents as control values (func- (2) Clinical concentrations of emetic drugs do not inhibit tional endpoints) is often not suitable for the detection the function of human 5-HT3A receptors. Some eme- of a mechanism like competition at the agonist bind- togenic drugs facilitate the function of 5-HT3A receptors. ing site, since binding and especially unbinding of (3) Indirect mechanisms, affecting 5-HT3 receptors by a competitor might take seconds or even minutes. We changes in the 5-HT concentration might underlie observed such problem with metoclopramide, which (anti)emesis. was characterized as a noncompetitive antagonist us- (4) The decision, which molecular mechanism is valid ing fast patch-clamp experiments, contrasting our for a drug-receptor interaction, is dependent on the radioligand binding results [Walkembach et al., Br choice of a functional endpoint that considers the kinet- J Pharmacol, 2005; Walkembach et al., in: Basic and ics of this mechanism. Systematic Mechanisms of Anesthesia, Ed. Mashimo, Ogli, Uchida, International Congress Series, 2005]. Acknowledgments: Supported by the DFG (BA 1454). We thank N. Lenssen for his help Conclusions. Our results suggest that: in some experiments. Norepinephrine transporter knockout-induced gene regulation Heinz Bönisch1, Marta Dziedzicka-Wasylewska2, Zofia Rogó¿2, Maciej Kuœmider2, Agata Faron-Górecka2, Edmund Przegaliñski2, Mina Kouta1, Britta Hänisch1, Michael Brüss1, Ralf Gilsbach1 Institute of Pharmacology and Toxicology, University of Bonn, Reuterstr. 2b, D-53113 Bonn, Germany; Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland; e-mail: [email protected] The norepinephrine transporter (NET) located in the mun, 1995]. The NET is a target for psychostimulants plasma membrane of noradrenergic neurons is re- (e.g. cocaine and amphetamine) and it is the primary sponsible for the rapid re-uptake of released norepi- target for clinically important antidepressants such as nephrine (NE). This enables fine tuning of noradren- the tricyclic antidepressants desipramine or nortrip- ergic neurotransmission and may prevent rapid desen- tyline or the selective norepinephrine re-uptake in- sitization of pre- and postsynaptic adrenoceptors. The hibitor (SNRI)

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