Interaction of the central analgesic, tramadol, with the uptake and release of 5‐hydroxytryptamine in the rat brain in vitro

1 Tramadol is a centrally acting analgesic with low opioid receptor affinity and therefore presumably other mechanisms of analgesic action. Tramadol inhibits noradrenaline uptake but since 5‐hydroxytryptamine (5‐HT) is also involved in the modulation of pain perception, we tested the effects of tramadol on 5‐HT uptake and release in vitro . 2 Tramadol inhibited the uptake of [ 3 H]‐5‐HT into purified rat frontal cortex synaptosomes with an IC 50 of 3.1 μ m . The (+)‐enantiomer was about four times more potent than the (−)‐enantiomer; the main metabolite of tramadol, O‐desmethyltramadol, was about ten times less potent. 3 Rat frontal cortex slices were preincubated with [ 3 H]‐5‐HT, then superfused and stimulated electrically. Tramadol facilitated the basal outflow of [ 3 H]‐5‐HT, at concentrations greater than 1 μ m , while the uptake inhibitor 5‐nitroquipazine enhanced both basal and stimulation‐evoked overflow. Effects of the (+)‐enantiomer were more potent than either the racemate, the (−)‐enantiomer or the principal metabolite. 4 The effects of tramadol on the basal outflow of [ 3 H]‐5‐HT were almost completely abolished when the superfusion medium contained a high concentration of the selective 5‐HT uptake blocker, 6‐nitroquipazine. 5 The results provide evidence for an interaction of tramadol with the neuronal 5‐HT transporter. An intact uptake system is necessary for the enhancement of extraneuronal 5‐HT concentrations by tramadol indicating an intraneuronal site of action.