Morphine-6-glucuronide is more mu-selective and potent in analgesic tests than morphine

Abstract

6-glucuronidation of morphine confers to this widely used analgesic increased potencies both in terms of receptor binding (selectivity) and of antinociceptive properties. In binding studies, 6-glucuronidation of morphine results in increased mu/kappa selectivity (comparable to DAGO). Na+ ions and Gpp(NH)p inhibit similarly the binding of morphine and M6G at the mu sites, suggesting that M6G is a mu agonist. The agonist nature of M6G was further confirmed by its antinociceptive properties: M6G (i.c.v.) was considerably more potent than morphine in the writhing (45 fold) and in the tail-flick (61 fold) tests. Furthermore, M6G induced a longer lasting analgesic effect than morphine. These data strongly suggest that M6G may significantly contribute to the pharmacological activity of morphine.