Morphine-6-glucuronide: a potent stimulator of locomotor activity in mice

The present study tested the hypothesis that morphine glucuronides have stimulant properties by studying their effects on locomotor activity in mice. Drug-naive C57BL/6J male mice were injected with saline, morphine, morphine-6-glucuronide (M6G) or morphine-3-glucuronide (M3G). In some experiments, mice were injected with saline or naloxone 5 min prior to drug treatment. Injection of 40 mg/kg morphine or M6G, but not M3G, significantly increased activity versus saline. The extent of activation induced by M6G was markedly higher than for morphine. Subsequent dose-response studies across a somewhat lower dose range using equimolar doses of morphine and M6G (3-80 mumoles/kg) found that both drugs significantly increased locomotor activity beginning at 20 mumoles/kg. M6G increased locomotor activity from 1.3 to 2.1 times more than for equimolar doses of morphine. Pretreatment with naloxone (10 mg/kg) completely abolished the locomotor stimulation induced by 32 mumoles/kg morphine and M6G. These findings present evidence that M6G is an active metabolite of morphine which has behaviorally stimulating effects and may play an important role in mediating the reinforcing properties of morphine in humans.