Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors:: A possible mechanism for tramadol-induced early emesis

([H-3]5-HT)-uptake and patch-clamp techniques were used to study the actions of (+) and (-) tramadol and the active metabolites of tramadol, (+) and (-) O-demethyl-tramadol on the human serotonin (5-HT) transporter and the human 5-HT3A receptor, stably expressed in HEK-293 cells. The (+) and (-) enantiomers of tramadol suppressed the human 5-HT transporter concentration-dependently (IC50= 1.0 and 0.8 mu M, respectively), resulting in 97% and 87% transport inhibition at their respective initial plasma concentrations (9.5 mu M). The (+) and (-) enantiomers of the active tramadol metabolite were less potent than tramadol in inhibiting the human 5-HT transporter (IC50= 15 and 44 mu M, respectively), resulting in 19.2% and 4.8% transport inhibition at their highest plasma concentrations (2.5 mu M). In contrast to their potent suppression of the 5-HT transporter, both, (+) and (-) tramadol inhibited 5-HT (30 mu M)-induced currents only at substantially higher concentrations (IC50= 199 and 251 mu M, respectively), resulting in only 6% and 4% inhibition at the initial maximum plasma concentration. A similar low potent inhibition of human 5-HT3A receptors was found for (+) and (-) O-deniethyl-tramadol (IC50=158 and 63 mu M, respectively). In conclusion, at clinical plasma concentrations tramadol potently suppresses the human 5-HT transporter, whereas it has only a slight effect on the human 5-HT3A receptor. The results are compatible with a possible mechanism for tramadol-induced early emesis involving the serotonergic system. (c) 2005 Elsevier B.V. All rights reserved.