Comparison of the discriminative and antinociceptive effects of morphine and its glucuronide metabolites after central or systemic administration in the rat

Abstract

 The potential of centrally (ICV) or systemically (SC) administered M6G to substitute for morphine in a drug discrimination task was characterized in the present study. Rats with a cannula in the lateral cerebral ventricle were trained to discriminate between injections of morphine (3 mg/kg, SC) and saline using a discrete-trial avoidance/escape procedure. Substitution tests were conducted with SC or ICV morphine, morphine-3-β-d-glucuronide (M3G), or morphine-6-β-d-glucuronide (M6G) and response latency in a tail-flick test was measured before each session began. The stimulus effects of morphine (ED₅₀=1.02 mg/kg SC or 2.1 μg/kg ICV) were fully shared by M6G, with potency dependent on route of administration (ED₅₀=3.12 mg/kg SC or 0.34 μg/kg ICV). The stimulus effects of M6G were highly correlated with its antinociceptive activity (r=0.84 SC or 0.46 ICV) and, at equipotent systemic doses, they lasted longer (t1/2=391 min) than those of morphine (t1/2=185 min). M3G was inactive in both procedures by both routes of administration. Naltrexone SC, given 30 min prior to testing, completely attenuated the stimulus effects of ICV M6G (AD₅₀=0.011 mg/kg), indicating that they are mediated by opioid receptors. The results of this study suggest that M6G might contribute to the interoceptive effects of morphine that underlie its potential for abuse.