title: Involvement of mu-opioid receptors in antinociception and inhibition of gastrointestinal transit induced by 7-hydroxymitragynine, isolated from Thai herbal medicine Mitragyna speciosa.
abstract: 7-hydroxymitragynine, a constituent of the Thai herbal medicine Mitragyna speciosa, has been found to have a potent opioid antinociceptive effect. In the present study, we investigated the mechanism of antinociception and the inhibitory effect on gastrointestinal transit of 7-hydroxymitragynine, and compared its effects with those of morphine. When administered subcutaneously to mice, 7-hydroxymitragynine produced antinociceptive effects about 5.7 and 4.4 times more potent than those of morphine in the tail-flick (ED50=0.80 mg/kg) and hot-plate (ED50=0.93 mg/kg) tests, respectively. The antinociceptive effect of 7-hydroxymitragynine was significantly blocked by the mu1/mu2-opioid receptor antagonist beta-funaltrexamine hydrochloride (beta-FNA) and the mu1-opioid receptor-selective antagonist naloxonazine in both tests. Thus, 7-hydroxymitragynine acts predominantly on mu-opioid receptors, especially on mu1-opioid receptors. Isolated tissue studies further supported its specificity for the mu-opioid receptors. Further, 7-hydroxymintragynine dose-dependently (ED50=1.19 mg/kg, s.c.) and significantly inhibited gastrointestinal transit in mice, as morphine does. The inhibitory effect was significantly antagonized by beta-FNA pretreatment, but slightly antagonized by naloxonazine. The ED50 value of 7-hydroxymitragynine on gastrointestinal transit was larger than its antinociceptive ED50 value. On the other hand, morphine significantly inhibits gastrointestinal transit at a much smaller dose than its antinociceptive dose. These results suggest that mu-opioid receptor mechanisms mediate the antinociceptive effect and inhibition of gastrointestinal transit. This compound induced more potent antinociceptive effects and was less constipating than morphine.
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane, Chiba 283-8555, Japan. kenjiro@jiu.ac.jp
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hatori
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Murayama
authors.forename: Kimihito
authors.initials: K
authors.lastname: Tashima
authors.forename: Sumphan
authors.initials: S
authors.lastname: Wongseripipatana
authors.forename: Kaori
authors.initials: K
authors.lastname: Misawa
authors.forename: Mariko
authors.initials: M
authors.lastname: Kitajima
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takayama
authors.forename: Syunji
authors.initials: S
authors.lastname: Horie
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005772:Gastrointestinal Transit / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D029001:Herbal Medicine; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D032065:Mitragyna / Q000737:chemistry*; D015394:Molecular Structure; D009020:Morphine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D010147:Pain Measurement / Q000379:methods; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000502:physiology*; D046948:Secologanin Tryptamine Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013785:Thailand; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009294:Narcotics; D017450:Receptors, Opioid, mu; D046948:Secologanin Tryptamine Alkaloids; C482678:7-hydroxymitragynine; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine