STUDIES ON THE POSSIBLE ROLE OF PHARMACOKINETICS IN THE DEVELOPMENT OF TOLERANCE TO MORPHINE IN THE RAT

1. The possible role of pharmacokinetics of morphine in the development of tolerance to the analgesic and hyperthermic effects of morphine was studied in the rat. 2. Male Sprague-Dawley rats were made tolerant to morphine by implanting 6 morphine pellets each containing 75 mg of morphine base for 7 days. The assessment of the degree of tolerance to morphine and pharmacokinetic parameters were done 72 hr after pellet removal. 3. Tolerance developed to both the analgesic and hyperthermic effects of morphine as evidenced by decreased responses to morphine in morphine pellet implanted rats compared with placebo pellet implanted rats. 4. The pharmacokinetic parameters, AUC0-->infinity, C(max), t1/2, k, MRT, V(ss) and Cl(t) were determined after injecting 5 and 10 mg/kg doses of morphine intravenously to placebo and morphine pellet implanted rats and using a highly sensitive and specific RIA method to quantitate serum levels of morphine. For a 5 mg/kg dose of morphine, the AUC0-->infinity and t1/2 in morphine pellet implanted rats were significantly higher than in placebo pellet implanted rats, but the k value was lower. The other pharmacokinetic parameters for morphine in the two treatment groups did not differ. For 10 mg/kg dose, the only change was an increase in the MRT in morphine tolerant rats when compared to nontolerant rats. 5. The results establish that the development of tolerance to the analgesic and hyperthermic effects of morphine is not related to pharmacokinetics of morphine in serum but may be related to modification of receptor systems in the central nervous system.