Raffa R B, Friderichs E, Reimann W, Shank R P, Codd E E, Vaught J L, Jacoby H I, Selve N
R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania.
J Pharmacol Exp Ther. 1993 Oct;267(1):331-40.
The explanation for the co-existence of opioid and nonopioid components of tramadol-induced antinociception appears to be related to the different, but complementary and interactive, pharmacologies of its enantiomers. The (+) enantiomer had Ki values of only 1.33, 62.4 and 54.0 microM at mu, delta and kappa receptors, respectively. The (-) enantiomer had even lower affinity at the mu and delta sites (Ki = 24.8, 213 and 53.5 microM, respectively. The (+) enantiomer was the most potent inhibitor of serotonin uptake (Ki = 0.53 microM) and the (-) enantiomer was the most potent inhibitor of norepinephrine uptake (Ki = 0.43 microM). Basal serotonin release was preferentially enhanced by the (+) enantiomer and stimulation-evoked norepinephrine release was preferentially enhanced by the (-) enantiomer. The (+) and (-) enantiomers each independently produced centrally mediated antinociception in the acetylcholine-induced abdominal constriction test (ED50 = 14.1 and 35.0 micrograms i.t., respectively). Racemic tramadol was significantly more potent (P < .05) than the theoretical additive effect of the enantiomers (antinociceptive synergy). Synergy was also demonstrated (P < .1) in the mouse 55 degrees C hot-plate test (i.p. route) and (P < .05) the rat Randall-Selitto yeast-induced inflammatory nociception model (i.v. and i.p. routes). Critically, the enantiomers interacted less than synergistically in two side-effects of inhibition of colonic propulsive motility and impairment of rotarod performance. The racemate and the (+) enantiomer were active in a chronic (arthritic) inflammatory pain model. Taken together, these findings provide a rational explanation for the coexistence of dual components to tramadol-induced antinociception and might form the basis for understanding its clinical profile.
曲马多诱导的镇痛作用中阿片样物质和非阿片样物质成分共存的原因似乎与其对映体不同但互补且相互作用的药理学特性有关。（+）对映体在μ、δ和κ受体处的Ki值分别仅为1.33、62.4和54.0微摩尔。（-）对映体在μ和δ位点的亲和力更低（分别为Ki = 24.8、213和53.5微摩尔）。（+）对映体是最有效的5-羟色胺摄取抑制剂（Ki = 0.53微摩尔），而（-）对映体是最有效的去甲肾上腺素摄取抑制剂（Ki = 0.43微摩尔）。基础5-羟色胺释放优先被（+）对映体增强，而刺激诱发的去甲肾上腺素释放优先被（-）对映体增强。在乙酰胆碱诱导的腹部收缩试验中，（+）和（-）对映体各自独立产生中枢介导的镇痛作用（ED50分别为14.1和35.0微克鞘内注射）。消旋曲马多比其对映体的理论相加效应显著更有效（P <.05）（镇痛协同作用）。在小鼠55℃热板试验（腹腔注射途径）中也证明了协同作用（P <.1），在大鼠Randall-Selitto酵母诱导的炎性疼痛模型（静脉注射和腹腔注射途径）中也证明了协同作用（P <.05）。至关重要的是，在抑制结肠推进性运动和损害转棒性能这两种副作用方面，对映体之间的相互作用小于协同作用。消旋体和（+）对映体在慢性（关节炎）炎性疼痛模型中具有活性。综上所述，这些发现为曲马多诱导的镇痛作用中双重成分的共存提供了合理的解释，并可能构成理解其临床特征的基础。
