EXPLANATION AT THE OPIOID RECEPTOR LEVEL FOR DIFFERING TOXICITY OF MORPHINE AND MORPHINE 6-GLUCURONIDE

The radiolabelled opioid receptor binding affinities of morphine and its active metabolite morphine 6-glucuronide at the total mu, mu-1, mu-2 and delta-receptors were determined. Morphine 6-glucuronide was found to have a 4-fold lower affinity for the mu 2 receptor (IC50 17 nM and 82 nM for morphine and morphine 6-glucuronide respectively, P = 0.01), the receptor postulated to be responsible for mediating the respiratory depression and gastrointestinal effects after morphine. This provides a possible explanation for the reduced respiratory depression and vomiting seen following morphine 6-glucuronide in man. A similar reduction in affinity of morphine 6-glucuronide was seen at the total mu receptor whilst there was no significant difference seen at the mu-1 or delta-receptor. Hence the increased analgesic potency of morphine 6-glucuronide over morphine remains unexplained.