EFFECT OF PRIOR MORPHINE-3-GLUCURONIDE EXPOSURE ON MORPHINE DISPOSITION AND ANTINOCICEPTION

Morphine-3-glucuronide (M3G), the primary metabolite of morphine in hu mans and rats, has been reported to antagonize morphine-induced pharma cologic effects. The present experiment was conducted to evaluate the effect of prior systemic M3G exposure on morphine disposition and anti nociceptive 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. b olus (2 mg/kg). Tail-flick latencies in response to hot water (50 degr ees) were assessed prior to and for 180 min after the morphine test do se. M3G exposure had no significant effect on morphine pharmacokinetic s, although a disproportionate increase in M3G concentrations was obse rved following the morphine i.v. bolus dose in rats infused with high dose M3G. Morphine-induced antinociception, expressed as the percent o f maximum response (%MPR), was maximum 15 min after morphine administr ation and returned to baseline by 180 min. A pharmacokinetic-pharmacod ynamic model was constructed to relate tail-flick latencies to morphin e serum concentrations. In saline-exposed rats, the antinociceptive re sponse to morphine was characterized by a sigmoidal E-max model, with an EC50 of 328 ng/mL, a Hill coefficient (gamma) of 4.5, and a half-li fe for the offset of pharmacologic effect of 11 min. No statistically significant differences in the intensity or duration of morphine-induc ed response were detected between saline- and M3G-exposed animals. The se results suggest that systemic formation of M3G is unlikely to contr ibute significantly to the development of tolerance to morphine antino ciception. (C) 1997 Elsevier Science Inc.