Role of morphine glucuronide metabolites in morphine dependence in the rat.

Concentrations of morphine and its 3- and 6-glucuronide metabolites (M3G and M6G) in plasma, brain, and urine of rats exposed to morphine for either 24 or 48 h were measured using high-performance liquid chromatography. In another group of morphine-treated rats, the intensity of naloxone-precipitated withdrawal behaviours was monitored at 24 and 48 h. The behavioural effects of M3G in opiate-naive and opiate-dependent rats were also investigated. Morphine was present in plasma, urine, and brain at 24 and 48 h, whereas M3G was detected in plasma and urine only. M6G was not present in detectable quantities in either plasma, urine, or brain. Although plasma concentrations of M3G were similar in both time groups, rats treated for 48 h had significantly larger quantities of M3G in their urine than did the other treatment groups. The incidence of withdrawal behaviour was significantly higher in animals exposed to morphine for 48 h than in those with only 24 h of exposure, M3G had no behavioural effects in the opiate-naive rats and did not precipitate an opiate-abstinence syndrome in morphine-dependent rats. From these results, it was concluded that although M3G is the major product formed by morphine breakdown in rats, it is unlikely that it is involved in the development of morphine dependence in this species.