Morphine-3-glucuronide inhibits morphine induced, but enhances morphine-6-glucuronide induced locomotor activity in mice

The main metabolite of morphine, morphine-3-glucuronide (M3G) has no opioid effects. Some studies have rather indicated that it antagonizes the antinociceptive and respiratory depressive effects of both morphine and the active metabolite morphine-6-glucuronide (M6G). We studied the possible influence of M3G on the psychostimulant properties of morphine and M6G measured by locomotor activity. Mice were given two injections, one with either 80, 240 or 500 mu mol/kg M3G or saline followed by an injection of 20 or 30 mu mol/kg morphine or M6G. M3G influenced the locomotor activity induced by both morphine and M6G, but in opposite directions. M3G reduced the morphine induced locomotor activity during the first hour following morphine injection in a concentration dependent manner. M3G pretreatment did not significantly influence brain concentrations of morphine indicating that the interaction was of a pharmacodynamic type. In contrast M3G pretreatment increased the M6G induced locomotor activity. M3G pretreatment increased serum and brain M6G concentrations to an extent indicating that this interaction was mainly of a pharmacokinetic type. In conclusion our results disclose complicated interactions between morphine and its two metabolites with respect to induction of locomotor activity and possibly also with respect to mechanisms related to drug reward. (c) 2007 Elsevier Inc. All rights reserved.