title: Differential antagonism of endomorphin-1 and endomorphin-2 spinal antinociception by naloxonazine and 3-methoxynaltrexone.
abstract: To determine the role of spinal mu-opioid receptor subtypes in antinociception induced by intrathecal (i.t.) injection of endomorphin-1 and -2, we assessed the effects of beta-funaltrexamine (a selective mu-opioid receptor antagonist) naloxonazine (a selective antagonist at the mu(1)-opioid receptor) and a novel receptor antagonist (3-methoxynaltrexone) using the paw-withdrawal test. Antinociception of i.t. endomorphins and [D-Ala(2), MePhe(4), Gly(ol)(5)]enkephalin (DAMGO) was completely reversed by pretreatment with beta-funaltrexamine (40 mg/kg s.c.). Pretreatment with a variety of doses of i.t. or s.c. naloxonazine 24 h before testing antagonized the antinociception of endomorphin-1, -2 and DAMGO. Judging from the ID(50) values of naloxonazine, the antinociceptive effect of endomorphin-2 was more sensitive to naloxonazine than that of endomorphin-1 or DAMGO. The selective morphine-6beta-glucuronide antagonist, 3-methoxynaltrexone, which blocked endomorphin-2-induced antinociception at each dose (0.25 mg/kg s.c. or 2.5 ng i.t.) that was inactive against DAMGO, did not affect endomorphin-1-induced antinociception but shifted the dose-response curve of endomorphin-2 3-fold to the right. These findings may be interpreted as indicative of the existence of a novel mu-opioid receptor subtype in spinal sites, where antinociception of morphine-6beta-glucuronide and endomorphin-2 are antagonized by 3-methoxynaltrexone. The present results suggest that endomorphin-1 and endomorphin-2 may produce antinociception through different subtypes of mu-opioid receptor.
authors.affiliation: Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, 981-8558, Sendai, Japan. s-sakura@tohoku-pharm.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Sakurada
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: M
authors.initials: M
authors.lastname: Yuhki
authors.forename: T
authors.initials: T
authors.lastname: Fujimura
authors.forename: K
authors.initials: K
authors.lastname: Murayama
authors.forename: A
authors.initials: A
authors.lastname: Yonezawa
authors.forename: C
authors.initials: C
authors.lastname: Sakurada
authors.forename: M
authors.initials: M
authors.lastname: Takeshita
authors.forename: J E
authors.initials: JE
authors.lastname: Zadina
authors.forename: A J
authors.initials: AJ
authors.lastname: Kastin
authors.forename: T
authors.initials: T
authors.lastname: Sakurada
mesh_terms: D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors; D000818:Animals; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000037:antagonists & inhibitors; D003932:Heroin / Q000819:agonists*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009842:Oligopeptides / Q000037:antagonists & inhibitors*; D010147:Pain Measurement / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors*
chemical_list: C107547:3-methoxynaltrexone; D000701:Analgesics, Opioid; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; C105294:endomorphin 2; D009271:Naltrexone; D003932:Heroin; C034643:naloxonazine