Previous studies have shown that morphine-6-glucuronide (M6G), a metabolite of morphine, induces reward and psychomotor stimulation but the role of the mu opioid receptor in these actions of the drug is not fully characterized. Thus, using mice lacking exon-2 of the mu opioid receptor and their wild-type littermates/controls, we determined the role of this receptor in psychomotor stimulation, sensitization, and conditioned place preference (CPP) induced by M6G. For comparison, we also assessed the role of the mu opioid receptor in the rewarding action of morphine. For the measurement of locomotor activity and sensitization, mice were habituated to motor activity chambers for 1h, then injected with M6G (10mg/kg) and locomotor activity was recorded for an additional 1h. The same treatment was given for five days and mice were tested for sensitization a week later. For the CPP experiments, mice were tested for baseline place preference on day 1, then received single or repeated alternate-day saline/drug or drug/saline conditioning and tested for CPP the following day. Mice were also tested for CPP under a drugged state. M6G induced psychomotor stimulation, a response that was enhanced upon repeated administration of the drug, showing that locomotor sensitization developed to the motor stimulatory action of M6G. However, M6G induced a weaker CPP response compared to morphine. None of these actions of M6G was detected in mice lacking the mu opioid receptor. Together, the current results suggest that M6G induces psychomotor stimulation and a weaker rewarding action via the mu opioid receptor.
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