title: Mu opioid receptor-dependent and independent components in effects of tramadol.
abstract: Tramadol is thought to induce analgesia via both opioid and non-opioid pathways, although the precise mechanisms remain to be elucidated. In this study, we investigated the roles of the mu-opioid receptor (MOP) in analgesic and rewarding effects of tramadol by using MOP knockout (KO) mice. Tramadol-induced antinociception, assessed by hot-plate and tail-flick tests, was significantly reduced in heterozygous and homozygous MOP-KO mice when compared with that in wild-type mice. Interestingly, however, tramadol retained its ability to induce significant antinociception in homozygous MOP-KO mice. The tramadol-induced antinociception remaining in homozygous MOP-KO mice was not significantly affected by methysergide, a serotonin receptor antagonist, but was partially blocked by yohimbine, an adrenaline alpha2 receptor antagonist, and both naloxone, a non-selective opioid receptor antagonist, and yohimbine. In addition, antinociceptive effects of an active tramadol metabolite M1 were abolished or remarkably reduced in MOP-KO mice. On the other hand, neither wild-type nor homozygous MOP-KO mice showed significant place preference for tramadol in a conditioned place preference test, although there were slight tendencies toward preference in wild-type mice and avoidance in homozygous MOP-KO mice. These results strongly support the idea suggested in the previous pharmacological studies that MOP and the adrenaline alpha2 receptor mediate most of the analgesic properties of tramadol.
authors.affiliation: Division of Psychobiology, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ide
authors.forename: Masabumi
authors.initials: M
authors.lastname: Minami
authors.forename: Kumatoshi
authors.initials: K
authors.lastname: Ishihara
authors.forename: George R
authors.initials: GR
authors.lastname: Uhl
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sora
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy*; D008784:Methysergide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009294:Narcotics / Q000627:therapeutic use*; D010147:Pain Measurement / Q000379:methods; D011930:Reaction Time / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000502:physiology*; D012201:Reward; D012702:Serotonin Antagonists / Q000494:pharmacology; D013997:Time Factors; D014147:Tramadol / Q000627:therapeutic use*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; C106029:M1 cyclosporin metabolite; D009294:Narcotics; D017450:Receptors, Opioid, mu; D012702:Serotonin Antagonists; D015016:Yohimbine; D014147:Tramadol; D016572:Cyclosporine; D008784:Methysergide