STUDIES ON MORPHINE TOLERANCE IN MICE. I. IN VIVO N-DEMETHYLATION OF MORPHINE AND N- AND O-DEMETHYLATION OF CODEINE

¹ Cardiovascular Research Institute and Department of Pharmacology, University of California San Francisco Medical Center, San Francisco, California

In order to establish whether development of tolerance to morphine leads to a decrease in N-demethylation of narcotic analgetics in the intact animal as has been shown by many investigators to occur for liver microsomal preparations, mice were made tolerant to 230 to 500 mg/kg of morphine per day by subcutaneous implantation of pellets of morphine. These mice and control mice were then injected with challenging doses of 5 mg/kg of morphine-N-C¹⁴H₃ or 33 mg/kg of codeine-N-C¹⁴H₃ or codeine-O-C¹⁴H₃; expired C¹⁴O₂, collected at 1- or 4-hr intervals up to 24 hr after injection of the labeled drug, served as a measure of demethylation. In no case did tolerance reduce demethylation, and, in fact, N-demethylation of codeine was greatly increased (from 27-31% of the dose in control mice to 45-56% of the dose in tolerant mice). An increase was found also in O-demethylation of codeine (from 24-25% of the dose to 32-36%). No difference was found between tolerant and control animals in N-demethylation of morphine, with the range of values of 1.2 to 2.4% of the dose demethylated in the control group completely overlapping the values of 1.5 to 2.0% for the tolerant group. These results do not support the current view that tolerance is characterized by reduced hepatic microsomal enzyme synthesis; alternate hypotheses are advanced that favor the concepts of either induction of or no change in synthesis of demethylating enzymes after the development of morphine tolerance.