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.
([3H]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 microM, respectively), resulting in 97% and 87% transport inhibition at their respective initial plasma concentrations (9.5 microM). The (+) and (-) enantiomers of the active tramadol metabolite were less potent than tramadol in inhibiting the human 5-HT transporter (IC50=15 and 44 microM, respectively), resulting in 19.2% and 4.8% transport inhibition at their highest plasma concentrations (2.5 microM). In contrast to their potent suppression of the 5-HT transporter, both, (+) and (-) tramadol inhibited 5-HT (30 microM)-induced currents only at substantially higher concentrations (IC50=199 and 251 microM, respectively), resulting in only 6% and 4% inhibition at the initial maximum plasma concentration. A similar low potent inhibition of human 5-HT(3A) receptors was found for (+) and (-) O-demethyl-tramadol (IC50=158 and 63 microM, 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.
Barann
Martin
M
Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany. martin.barann@ukb.uni-bonn.de
Urban
Bernd
B
Stamer
Ulrike
U
Dorner
Zita
Z
Bönisch
Heinz
H
Brüss
Michael
M
D000701:Analgesics, Opioid / Q000494:pharmacology; D002460:Cell Line; D015283:Citalopram / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014147:Tramadol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014316:Tritium; D014839:Vomiting / Q000209:etiology / Q000503:physiopathology
D000701:Analgesics, Opioid; D015283:Citalopram; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014147:Tramadol; D014316:Tritium; C080580:O-demethyltramadol