Antagonism of heroin and morphine self-administration in rats by the morphine-6β-glucuronide antagonist 3-O-methylnaltrexone

In mice, 3-O-methylnaltrexone blocks the analgesic actions of morphine-6 beta-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-6 beta-glucuronide opioid receptor in the reinforcing properties of heroin and morphine. (C) 1999 Elsevier Science B.V. All rights reserved.