title: Effects of opioids on human serotonin transporters.
abstract: The serotonin (5-hydroxtryptamine, 5-HT) system plays a role in analgesia and emesis. The aim of this study was to test whether opioids or ketamine inhibit the human 5-HT transporter and whether this increases free plasma 5-HT concentrations. HEK293 cells, stably transfected with the human 5-HT transporter cDNA, were incubated with morphine, hydromorphone, fentanyl, alfentanil, pethidine (meperidine), tramadol, ketamine, and the reference substance citalopram (specific 5-HT transporter inhibitor). The uptake of [(3)H]5-HT was measured by liquid scintillation counting. In a second series of experiments, study drugs were incubated with plasma of ten healthy blood donors and change of 5-HT plasma-concentrations were measured (ELISA). The end point was the inhibition of the 5-HT transporter by different analgesics either in HEK293 cells or in human platelets ex vivo. Tramadol, pethidine, and ketamine suppressed [(3)H]5-HT uptake dose-dependently with an IC50 of 1, 20.9, and 230 μM, respectively. These drugs also prevented 5-HT uptake in platelets with an increase in free plasma 5-HT. Free 5-HT concentrations in human plasma were increased by citalopram 1 μM, tramadol 20 μM, pethidine 30 μM, and ketamine 100 μM to 280 [248/312]%, 269 [188/349]%, and 149 [122/174]%, respectively, compared to controls without any co-incubation (means [95 % CI]; all p < 0.005). No change in both experimental settings was observed for the other opioids. Tramadol and pethidine inhibited the 5-HT transporter in HEK293 cells and platelets. This inhibition may contribute to serotonergic effects when these opioids are given in combination, e.g., with monoamine oxidase inhibitors or selective serotonin reuptake inhibitors.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Barann
authors.forename: U M
authors.initials: UM
authors.lastname: Stamer
authors.forename: M
authors.initials: M
authors.lastname: Lyutenska
authors.forename: F
authors.initials: F
authors.lastname: Stüber
authors.forename: H
authors.initials: H
authors.lastname: Bönisch
authors.forename: B
authors.initials: B
authors.lastname: Urban
mesh_terms: D015760:Alfentanil / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology; D005283:Fentanyl / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D004091:Hydromorphone / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008614:Meperidine / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology; D012701:Serotonin / Q000097:blood / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014147:Tramadol / Q000494:pharmacology
chemical_list: D015760:Alfentanil; D000701:Analgesics, Opioid; D015283:Citalopram; D005283:Fentanyl; D004091:Hydromorphone; D007649:Ketamine; D008614:Meperidine; D009020:Morphine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014147:Tramadol