methylnaltrexone and morphine-6-glucuronide

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.

Topics: Adenylyl Cyclases; Animals; Cocaine; Discrimination Learning; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Heroin; Heroin Dependence; Macaca mulatta; Male; Morphine; Morphine Derivatives; Naltrexone; Narcotics; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Self Administration

In mice, 3-O-methylnaltrexone blocks the analgesic actions of morphine-6beta-glucuronide and heroin at doses which are inactive against morphine. We found a similar selectivity in rats. 3-O-Methylnaltrexone antagonized the analgesic actions of 6-acetylmorphine in Sprague-Dawley rats and heroin in Wistar rats at doses that were inactive against morphine. Inclusion of a fixed dose of 3-O-methylnaltrexone significantly shifted the analgesic dose-response curves for 6-acetylmorphine and heroin without altering the morphine dose-response curves. In a self-administration model, 3-O-methylnaltrexone treatment significantly increased both heroin and morphine intake during the first hour, suggestive of an antagonist effect. This effect at doses of 3-O-methylnaltrexone which were inactive against morphine analgesia implied a role for the morphine-6beta-glucuronide opioid receptor in the reinforcing properties of heroin and morphine.

Topics: Animals; Conditioning, Operant; Dose-Response Relationship, Drug; Heroin; Injections, Subcutaneous; Male; Morphine; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Narcotics; Pain Measurement; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Rats, Wistar; Self Administration