title: Effects of tramadol stereoisomers on norepinephrine efflux and uptake in the rat locus coeruleus measured by real time voltammetry.
abstract: 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.
authors.affiliation: Academic Department of Anaesthesia and Intensive Care, St Bartholomew's and the Royal London School of Medicine and Dentistry, Royal London Hospital, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Halfpenny
authors.forename: L F
authors.initials: LF
authors.lastname: Callado
authors.forename: S E
authors.initials: SE
authors.lastname: Hopwood
authors.forename: T A
authors.initials: TA
authors.lastname: Bamigbade
authors.forename: R M
authors.initials: RM
authors.lastname: Langford
authors.forename: J A
authors.initials: JA
authors.lastname: Stamford
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D008125:Locus Coeruleus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014147:Tramadol / Q000494:pharmacology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D000701:Analgesics, Opioid; D007093:Imidazoles; D007211:Indoles; D054833:Isoindoles; D014147:Tramadol; D009638:Norepinephrine; C072125:BRL 44408