COMPLEMENTARY AND SYNERGISTIC ANTINOCICEPTIVE INTERACTION BETWEEN THEENANTIOMERS OF TRAMADOL

The explanation for the co-existence of opioid and nonopioid component s of tramadol-induced antinociception appears to be related to the dif ferent, but complementary and interactive, pharmacologies of its enant iomers. The (+) enantiomer had K(i) values of only 1.33, 62.4 and 54.0 muM at mu, delta and kappa receptors, respectively. The (-) enantiome r had even lower affinity at the mu and delta sites (K(i) = 24.8, 213 and 53.5 muM, respectively. The (+) enantiomer was the most potent inh ibitor of serotonin uptake (K(i) = 0.53 muM) and the (-) enantiomer wa s the most potent inhibitor of norepinephrine uptake (K(i) = 0.43 muM) . Basal serotonin release was preferentially enhanced by the (+) enant iomer and stimulation-evoked norepinephrine release was preferentially enhanced by the (-) enantiomer. The (+) and (-) enantiomers each inde pendently produced centrally mediated antinociception in the acetylcho line-induced abdominal constriction test (ED50 = 14.1 and 35.0 mug i.t ., respectively). Racemic tramadol was significantly more potent (P < .05) than the theoretical additive effect of the enantiomers (antinoci ceptive 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. r outes). Critically, the enantiomers interacted less than synergistical ly in two side-effects of inhibition of colonic propulsive motility an d impairment of rotarod performance. The racemate and the (+) enantiom er were active in a chronic (arthritic) inflammatory pain model. Taken together, these findings provide a rational explanation for the coexi stence of dual components to tramadol-induced antinociception and migh t form the basis for understanding its clinical profile.