Mu opioid receptor-dependent and independent components in effects of tramadol

Soichiro Ide, Masabumi Minami, Kumatoshi Ishihara, George R. Uhl, Ichiro Sora, Kazutaka Ikeda

Research output: Contribution to journalArticlepeer-review

102 Scopus citations


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 μ-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 α2 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 α2 receptor mediate most of the analgesic properties of tramadol.

Original languageEnglish (US)
Pages (from-to)651-658
Number of pages8
Issue number3
StatePublished - Sep 2006
Externally publishedYes


  • Adrenaline
  • Antinociception
  • Knockout mice
  • Opioid receptor
  • Reward
  • Tramadol

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology


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