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 mm prior to the administration of morphine by i.v. bolus (2 mg/kg). Tail-flick latencies in response to hot water (50°) 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 E(max) model, with an EC₅₀ of 328 ng/mL, a Hill coefficient (γ) 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.