Effect of prior morphine-3-glucuronide exposure on morphine disposition and antinociception

Morphine-3-glucuronide (M3G), the primary metabolite of morphine in humans and rats, has been reported to antagonize morphine-induced pharmacologic effects. The present experiment was conducted to evaluate the effect of prior systemic M3G exposure on morphine disposition and antinociceptive response in male Sprague-Dawley rats. Saline (N = 6), low dose M3G (0.15 mg/hr, N = 7), or high dose M3G (0.30 mg/hr, N = 6) was infused for 720 min prior to the administration of morphine by i.v. bolus (2 mg/kg). Tail-flick latencies in response to hot water (50 degrees) were assessed prior to and for 180 min after the morphine test dose. M3G exposure had no significant effect on morphine pharmacokinetics, although a disproportionate increase in M3G concentrations was observed following the morphine i.v. bolus dose in rats infused with high dose M3G. Morphine-induced antinociception, expressed as the percent of maximum response (%MPR), was maximum 15 min after morphine administration and returned to baseline by 180 min. A pharmacokinetic-pharmacodynamic model was constructed to relate tail-flick latencies to morphine serum concentrations. In saline-exposed rats, the antinociceptive response to morphine was characterized by a sigmoidal Emax model, with an EC50 of 328 ng/mL, a Hill coefficient (gamma) of 4.5, and a half-life for the offset of pharmacologic effect of 11 min. No statistically significant differences in the intensity or duration of morphine-induced response were detected between saline- and M3G-exposed animals. These results suggest that systemic formation of M3G is unlikely to contribute significantly to the development of tolerance to morphine antinociception.