title: Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol.
abstract: 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.
authors.affiliation: R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania.
authors.forename: R B
authors.initials: RB
authors.lastname: Raffa
authors.forename: E
authors.initials: E
authors.lastname: Friderichs
authors.forename: W
authors.initials: W
authors.lastname: Reimann
authors.forename: R P
authors.initials: RP
authors.lastname: Shank
authors.forename: E E
authors.initials: EE
authors.lastname: Codd
authors.forename: J L
authors.initials: JL
authors.lastname: Vaught
authors.forename: H I
authors.initials: HI
authors.lastname: Jacoby
authors.forename: N
authors.initials: N
authors.lastname: Selve
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000700:Analgesics / Q000737:chemistry*; D000818:Animals; D001168:Arthritis / Q000188:drug therapy; D004357:Drug Synergism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D014179:Neurotransmitter Uptake Inhibitors; D009638:Norepinephrine / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D011957:Receptors, Opioid / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014147:Tramadol / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000700:Analgesics; D014179:Neurotransmitter Uptake Inhibitors; D011957:Receptors, Opioid; D012701:Serotonin; D014147:Tramadol; D000109:Acetylcholine; D009638:Norepinephrine