Further evidence that morphine-6 beta-glucuronide is a more potent opioid agonist than morphine

The antinociceptive properties of morphine-6 beta-glucuronide (M6G) and morphine (oral, i.c.v. and s.c.) were examined in two tests involving different nociceptive stimuli [i.e., cutaneous-thermal (tail-flick) and chemical-visceral (acetic acid-writhing)] in both naive and chronically treated mice. Twenty min after i.c.v. injection, M6G was 47 and 360 times more potent than morphine in the writhing and tail-flick tests, respectively. This difference was not due to differences in affinity because M6G displayed lower apparent affinities (Ki) for mu and kappa binding sites in vitro. After systemic injection, the two opiates were equieffective, although M6G produced a 10-fold longer antinociceptive effect. These differences with route of administration partially result from the hydrophilic nature of M6G because its inflow into the brain compartment was at least 10-fold lower than that of morphine, whereas the rate of elimination of the parent molecule was 3 times greater. After chronic treatment, mice readily develop tolerance and marked physical dependence to the antinociceptive effects of M6G. In vivo binding studies showed that M6G exerts its antinociceptive effect at low (less than 1%) fractional occupancy of [3H]diprenorphine-specific binding sites. In contrast, morphine needs to occupy 9.5 (writhing) to 47 (tail-flick) times more opioid binding sites to produce the same antinociceptive activity. M6G thus appears to have greater pharmacological potency than morphine, which in comparison possesses a low intrinsic efficacy.