Morphine-3-glucuronide: silent regulator of morphine actions.

To assess whether stoichiometric manipulation of morphine (M) metabolism can enhance analgesia or slow the development of M tolerance we co-administered M-3- glucuronide (M3G) during single or repeated doses of morphine in rats. Although M3G itself lacked analgesic activity, co-injection of M3G with M increased and prolonged analgesia beyond that seen with M. In addition, diminution of the acute analgesic effect of M after 3 once-daily doses of M did not occur after daily co-injection of M3G and M. Thus the traditional view that tolerance to the effects of M is due solely to effects mediated through opioid receptors must be broadened to include the contributions of enzyme induction or stoichiometric equilibration of M3G in this process.