THE EFFECT OF ALTERING LIVER MICROSOMAL N-DEMETHYLASE ACTIVITY ON THE DEVELOPMENT OF TOLERANCE TO MORPHINE IN RATS

¹ New York State Research Institute for Neurochemistry and Drug Addiction, and College of Physicians and Surgeons, Columbia University, New York, N. Y.

The effect of various agents on the level of meperidine N-demethylase in rat liver and on the development of tolerance to daily morphine injections has been described. Minimal effects were found when nicotinamide was included in the drinking water. The level of the liver enzyme, depressed by chronic morphine treatment, was increased by the administration of phenobarbital or chlorpromazine. The administration of 19-nortestosterone to the morphinized rats increased the body weight, liver weight and protein level as well as the level of two drug-metabolizing enzymes found in the microsomal-supernatant fraction, the hexobarbital metabolizing enzyme and meperidine demethylase. The changes in microsomal demethylase activity were not directly related to changes in the rate of development of tolerance to morphine.