Morphine-6beta-glucuronide is a major metabolite of morphine. We wanted to examine whether the effects related to opiate CNS stimulation could be mediated by different receptors for morphine and M6G by studying the development of crosstolerance between these two drugs. The effect studied was locomotor activity in C57BL/6JBom mice. We observed a dose-dependent development of tolerance to daily injections of morphine, with 20 micromol/kg giving the most rapid development of tolerance, apparent already on the second day of treatment. This was also observed for the same dose of M6G. Crosstolerance to M6G was measured both after 1 day pretreatment and 7 days pretreatment with morphine 20 micromol/kg, while the crosstolerance to morphine was tested only after 1 day pretreatment with M6G (20 micromol/kg). Lack of crosstolerance towards M6G after 1 day of morphine pretreatment was observed, whereas crosstolerance to M6G was observed after 7 days of exposure to morphine pretreatment. Crosstolerance after M6G pretreatment to morphine was observed. It was concluded that the main part of the effect caused by M6G was mediated through a specific M6G receptor.