Morphine-6-glucuronide-induced locomotor stimulation in mice: role of opioid receptors.

Morphine-6beta-glucuronide is a major metabolite of morphine with potent analgesic actions. To explore the importance of this opiate when administered as a drug by its own or in morphine action, we studied the locomotor activity response to morphine and morphine-6-glucuronide in drug-naive C57 BL/6JBom mice. The effects of administration of the two opiates on a battery of 7 different locomotor activities were studied and compared to saline controls. A dose of 20 micromol/kg morphine-6-glucuronide resulted in more locomotion than the same dose of morphine, while at higher doses (up to 120 micromol/kg), similar increases for most locomotor behaviours were recorded for both drugs. Pretreatment with naltrindole indicated that the delta-receptors play an equivalent but minor role in mediating both morphine-6-glucuronide and morphine hyperlocomotion. Administration of high naltrexone doses (10 mg/kg) completely abolished the locomotor stimulation induced by both opiates. However, at intermediate naltrexone doses of 0.25 and 0.5 mg/kg, morphine-induced behaviours was completely inhibited while morphine-6-glucuronide induced behaviours demonstrated partial resistance to naltrexone inhibition. The mu1-specific receptor antagonist naloxonazine caused 75% reduction of morphine induced behaviours and only 50% inhibition of morphine-6-glucuronide induced behaviors. Taken together our observations indicated general similarity but also marked differences between morphine and morphine-6-glucuronide with respect to opiate receptors mediating the locomotor stimulatory effect.