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Effects of opioids on human serotonin transporters

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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 [3H]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 [3H]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.

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Acknowledgements

This study was funded by a grant of the Deutsche Forschungsgemeinschaft (DFG; BA 1454).

We thank Gundula Hesse, Zita Dorner, and Caroline von dem Bussche for helpful technical assistance.

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The authors declare that they have no conflict of interest.

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Correspondence to U. M. Stamer.

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M. Barann and U. M. Stamer, these authors contributed equally to this work.

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Barann, M., Stamer, U.M., Lyutenska, M. et al. Effects of opioids on human serotonin transporters. Naunyn-Schmiedeberg's Arch Pharmacol 388, 43–49 (2015). https://doi.org/10.1007/s00210-014-1056-3

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  • DOI: https://doi.org/10.1007/s00210-014-1056-3

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