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 analge sic 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 r acemic, (+)- 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. R acemic tramadol and its (+)- and (-)-enantiomers (all at 5 mu mol litre(-1) ) significantly increased stimulated norepinephrine efflux (P<0.01) by mean 66 (SEM 10)%, 57 (7)% and 64 (13)%, respectively. However, only (-)-tramad ol blocked norepinephrine reuptake (P<0.01), increasing the reuptake half-t ime to 499 (63)% of pre-drug values. The metabolite O-desmethyl tramadol wa s inactive at the concentration tested (5 mu mol litre(-1)). in the case of (-)-tramadol, the effect on norepinephrine efflux was directly proportiona l to, but significantly smaller than, the effect on norepinephrine uptake ( P<0.01). This appeared to be a result of compensatory alpha(2A) autorecepto r tone as the selective alpha(2A) autoreceptor antagonist BRL 44408 (1 mu m ol litre(-1)) eliminated this difference when its own effects on norepineph rine reuptake were taken into account. The efficacy of (-)-tramadol on nore pinephrine uptake, at clinically relevant concentrations, may contribute to its antinociceptive efficacy.