title: Opioid partial agonist effects of 3-O-methylnaltrexone in rhesus monkeys.
abstract: 3-O-Methylnaltrexone (3-MNTX), a putative antagonist of morphine-6-beta-d-glucuronide (M6G) receptors, has been reported to block the behavioral effects of heroin at doses that do not block those of morphine, suggesting that M6G receptors may play a unique role in the addictive properties of heroin. This study investigated the effects of 3-MNTX in monkeys trained to discriminate i.v. heroin from vehicle or to self-administer i.v. heroin under a progressive-ratio schedule. Additional in vitro studies determined the effects of 3-MNTX and reference drugs on adenylyl cyclase activity in caudate-putamen membranes of monkeys and rats. In drug discrimination experiments, heroin, morphine, and M6G substituted for heroin in all subjects, whereas 3-MNTX substituted for heroin in one-half the monkeys tested. In these latter monkeys, the effects of 3-MNTX were antagonized by naltrexone, and pretreatment with 3-MNTX enhanced the effects of heroin, M6G, and morphine, indicative of micro-agonist activity. In monkeys showing no substitution of 3-MNTX for heroin, 3-MNTX antagonized the effects of heroin, M6G, and morphine. In self-administration experiments, heroin and 3-MNTX maintained injections per session significantly above those maintained by vehicle when the initial response requirement (IRR) was low; only heroin maintained significant self-administration when the IRR was high. In vitro, 3-MNTX inhibited adenylyl cyclase activity in both monkey and rat brain membranes. The degree of inhibition produced by 3-MNTX was less than that produced by the full agonist [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO). The results suggest that 3-MNTX functions primarily as a partial agonist at micro-receptors in monkeys and do not support a singular role for M6G receptors in the abuse-related effects of heroin.
authors.affiliation: Harvard Medical School, New England Primate Research Center, Southborough, MA 01772-9102, USA. donna_platt@hms.harvard.edu
authors.forename: Donna M
authors.initials: DM
authors.lastname: Platt
authors.forename: James K
authors.initials: JK
authors.lastname: Rowlett
authors.forename: Sari
authors.initials: S
authors.lastname: Izenwasser
authors.forename: Roger D
authors.initials: RD
authors.lastname: Spealman
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D003932:Heroin / Q000494:pharmacology; D006556:Heroin Dependence / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009022:Morphine Derivatives / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012646:Self Administration
chemical_list: D009022:Morphine Derivatives; D009294:Narcotics; D000644:Quaternary Ammonium Compounds; D017450:Receptors, Opioid, mu; C032257:methylnaltrexone; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009271:Naltrexone; C035349:morphine-6-glucuronide; D003932:Heroin; D009020:Morphine; D000262:Adenylyl Cyclases; D003042:Cocaine