Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus

Abstract

Tramadol is an atypical centrally acting analgesic agent with relatively weak opioid receptor affinity in comparison with its antinociceptive efficacy. Evidence suggests that block of monoamine uptake may contribute to its analgesic actions. Therefore, we have examined the actions of (±)-tramadol, (+)tramadol, (-)-tramadol and O-desmethyltramadol (M1 metabolite) on electrically evoked 5-HT efflux and uptake in the dorsal raphe nucleus (DRN) brain slice, measured by fast cyclic voltammetry. Racemic tramadol and its (+)enantiomer (both 5 μmol litre-1) significantly blocked DRN 5-HT uptake (both p < 0.05) and increased stimulated 5-HT efflux(p < 0.01 (±)-tramadol; P < 0.05 (+)-tramadol). The (-)enantiomer and metabolite, O-desmethyltramadol, were inactive at the concentration tested (5 μmol litre-1). For both (±)-tramadol and the (+)enantiomer, the action on 5-HT efflux preceded an effect on 5-HT uptake, suggesting that uptake block was not the cause of the increased 5-HT efflux and that tramadol might therefore have a direct 5-HT releasing action. This activity, at clinically relevant concentrations, may help to explain the antinociceptive efficacy of tramadol despite weak μ opioid receptor affinity and adds to evidence that tramadol exerts actions on central mono-aminergic systems that may contribute to its analgesic effect.