Effect of Naloxone on the Morphine Concentration in the Central Nervous System and Plasma in Rats

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We investigated whether the distribution (concentration) of morphine in the central nervous system (CNS) after systemic administration could be an index for the in vivo binding of morphine. Neither the morphine concentration nor its decline correlated with the density of opiate receptors. Naloxone decreased the morphine concentration in some CNS regions and plasma after a high dose of morphine, but not after a small dose of morphine. The CNS regions in which naloxone decreased the morphine concentration did not correlate with the density of opiate receptors, and the concentration ratios (CNS regions versus plasma) of morphine were not affected by naloxone. These results suggested that the morphine concentration in the CNS did not reflect the in vivo binding of morphine and that the naloxone-induced decrease in morphine concentration was not due to a displacement of morphine from its receptor sites but due to a change in morphine kinetics. Pharmacokinetic studies suggested that naloxone decreased the morphine concentration through an increased volume of morphine distribution. This naloxone-induced decrease in morphine concentration may contribute to the naloxone-induced inhibition of morphine action in addition to the competitive antagonism at opiate receptors.