Effects of naltrexone on pharmacodynamics and pharmacokinetics of intravenously administered morphine in the rat

Effects of naltrexone administered intravenously on the pharmacological actions and kinetics of morphine in serum following intravenous administration of morphine were determined in male Sprague-Dawley rats. A 10 mg/kg dose of morphine produced an analgesic response as measured by the tail flick test. Morphine also produced a hyperthermic effect. Naltrexone dose (0.625-2.5 mg/kg)-dependently antagonized the analgesic and hyperthermic effects of morphine. The effect of naltrexone (0.625 and 2.5 mg/kg) on the pharmacokinetic parameters area under the serum morphine concentration time curve (AUC0--infinity), serum levels of morphine extrapolated to zero time (Cmax), half-life (t1/2), mean residence time (MRT), total body clearance (Clt), and volume of distribution at steady state (Vss) of morphine in serum was determined. Naltrexone (0.625 mg/kg) significantly increased AUC0--infinity, Cmax, t1/2 MRT, but decreased the Vss, elimination rate constant (k) and Clt. The higher dose of naltrexone (2.5 mg/kg) produced an increase in the Cmax value of morphine in the serum, but the other pharmacokinetic parameters were unaffected. Since increased morphine concentrations in serum produced by naltrexone cannot explain its antagonistic effects on analgesia and hyperthermia, it is concluded that naltrexone produces its effects by blocking opiate receptors at the appropriate sites. The increases in serum morphine levels by naltrexone may be related to displacement of morphine from protein binding sites and inhibition of morphine metabolism by glucuronyl transferase. This study for the first time demonstrates that in the rat, when morphine and naltrexone are given concurrently, although serum levels of morphine increase, pharmacological effects of morphine are antagonized.(ABSTRACT TRUNCATED AT 250 WORDS)