Halfpenny D M, Callado L F, Hopwood S E, Bamigbade T A, Langford R M, Stamford J A
Academic Department of Anaesthesia and Intensive Care, St Bartholomew's and the Royal London School of Medicine and Dentistry, Royal London Hospital, UK.
Br J Anaesth. 1999 Dec;83(6):909-15. doi: 10.1093/bja/83.6.909.
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.
尽管曲马多在结构上与可待因相似，但它是一种不同寻常的镇痛药，其抗伤害感受作用并非仅仅源于阿片样物质的作用，还因其具有明显的阻断单胺摄取的能力。曲马多是立体异构体的混合物。在本研究中，我们通过快速循环伏安法检测了外消旋体、（+）-和（-）-曲马多以及O-去甲基曲马多（主要人体代谢产物）对蓝斑脑片中电诱发去甲肾上腺素流出和摄取的作用。外消旋体曲马多及其（+）-和（-）-对映体（均为5 μmol/L）均显著增加了刺激后的去甲肾上腺素流出（P < 0.01），平均分别增加了66（标准误10）%（+）、57（7）%（-）和64（13）%（外消旋体）。然而，只有（-）-曲马多阻断了去甲肾上腺素的再摄取（P < 0.01），使再摄取半衰期增加至给药前值的499（63）%。代谢产物O-去甲基曲马多在所测试的浓度（5 μmol/L）下无活性。就（-）-曲马多而言，其对去甲肾上腺素流出的作用与对去甲肾上腺素摄取的作用直接相关，但显著小于后者（P < 0.01）。这似乎是由于代偿性α2A自身受体张力所致，因为在考虑其对去甲肾上腺素再摄取的自身作用后，选择性α2A自身受体拮抗剂BRL 44408（1 μmol/L）消除了这种差异。在临床相关浓度下，（-）-曲马多对去甲肾上腺素摄取的作用可能有助于其抗伤害感受作用。
