1. The centrally acting analgesic, tramadol, has low affinity for opioid receptors and therefore presumably other mechanisms of analgesic action. Neurotransmitter release and uptake experiments were used to characterize the effects of tramadol on the central noradrenergic and dopaminergic systems. 2. Tramadol inhibited the uptake of [3H]-noradrenaline into purified rat hypothalamic synaptosomes with an IC50 of 2.8 microM; the (-)-enantiomer was about ten times more potent than the (+)-enantiomer. Results with the principal metabolite O-desmethyltramadol were very similar. Inhibition of dopamine uptake into purified rabbit caudate nucleus synaptosomes was very weak with 62% inhibition of 100 microM. 3. Rat occipital cortex slices were preincubated with [3H]-noradrenaline and rabbit caudate nucleus slices with [3H]-dopamine, then superfused and stimulated electrically. Tramadol, 1 and 10 microM, enhanced the stimulation-evoked [3H]-noradrenaline overflow by 25 and 69%, respectively; the (-)-enantiomer was more potent than the racemate or the (+)-enantiomer. Tramadol, 10 microM, had no effect on dopamine release. 4. The effects of tramadol on the stimulation-evoked [3H]-noradrenaline release were abolished when uptake sites were already blocked by a high concentration of cocaine. 5. The metabolite O-desmethyltramadol showed a slight facilitation of the stimulation-evoked noradrenaline release; the effect was more pronounced in the presence of a high concentration of naloxone. In the presence of cocaine, inhibition of the release was observed similar to the effect of morphine but less potent. 6. The results show that tramadol blocks noradrenaline uptake with selectivity as compared to dopamine uptake. The interaction with the noradrenaline transporter is stereoselective. The principal metabolite O-desmethyltramadol shows in addition to noradrenaline uptake inhibition, opioid inhibition of noradrenaline release.