Effects of tramadol stereoisomers on norepinephrine efflux and uptake in the rat locus coeruleus measured by real time voltammetry.

Despite its structural similarity to codeine, tramadol is an unusual analgesic whose antinociceptive efficacy is not solely a result of opioid actions but also of its apparent capacity to block monoamine uptake. Tramadol is a mixture of stereoisomers. In this study, we have examined the actions of racemic, (+)- and (-)-tramadol, in addition to O-desmethyltramadol (the main human metabolite), on electrically evoked norepinephrine efflux and uptake in the locus coeruleus brain slice, measured by fast cyclic voltammetry. Racemic tramadol and its (+)- and (-)-enantiomers (all at 5 mumol litre-1) significantly increased stimulated norepinephrine efflux (P < 0.01) by mean 66 (SEM 10)%, 57 (7)% and 64 (13)%, respectively. However, only (-)-tramadol blocked norepinephrine reuptake (P < 0.01), increasing the reuptake half-time to 499 (63)% of pre-drug values. The metabolite O-desmethyl tramadol was inactive at the concentration tested (5 mumol litre-1). In the case of (-)-tramadol, the effect on norepinephrine efflux was directly proportional to, but significantly smaller than, the effect on norepinephrine uptake (P < 0.01). This appeared to be a result of compensatory alpha 2A autoreceptor tone as the selective alpha 2A autoreceptor antagonist BRL 44408 (1 mumol litre-1) eliminated this difference when its own effects on norepinephrine reuptake were taken into account. The efficacy of (-)-tramadol on norepinephrine uptake, at clinically relevant concentrations, may contribute to its antinociceptive efficacy.