Antagonism of heroin and morphine self-administration in rats by the morphine-6beta-glucuronide antagonist 3-O-methylnaltrexone.
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.
Walker
J R
JR
Department of Neuropharmacology, Scripps Research Institute, La Jolla, CA 92037, USA.
King
M
M
Izzo
E
E
Koob
G F
GF
Pasternak
G W
GW
D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D003932:Heroin / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000037:antagonists & inhibitors*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D000644:Quaternary Ammonium Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012646:Self Administration
D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D009294:Narcotics; D000644:Quaternary Ammonium Compounds; C032257:methylnaltrexone; D009271:Naltrexone; C035349:morphine-6-glucuronide; D003932:Heroin; D009020:Morphine