BIOCHEMICAL AND PHARMACOLOGICAL CHANGES IN THE RAT FOLLOWING CHRONIC ADMINISTRATION OF MORPHINE, NALORPHINE AND NORMORPHINE

TLDR

Chronic administration of morphine and morphine‑nalorphine mixtures to rats induces tolerance to morphine and diminishes liver enzymes’ ability to N‑dealkylate morphine and nalorphine, indicating that multiple enzymes participate in narcotic drug N‑dealkylation. The study proposes the N‑demethylating enzyme as a model for investigating narcotic‑drug receptor sites, based on the parallel decline in enzyme activity and analgesic response. Chronic nalorphine and normorphine treatment moderately reduces morphine analgesia (cross‑tolerance) and N‑demethylation of morphine by liver enzymes, while N‑dealkylation of nalorphine remains largely unaffected; the extent of tolerance and enzymatic depression depends on daily dose rather than duration.

Abstract

Chronic administration of morphine and morphine-nalorphine mixtures to the rat results in a profound diminution of the analgesic response to a test close of morphine (tolerance) and a profound reduction in the ability of liver enzyme preparations from these animals to N-dealkylate morphine and nalorphine. Moderate reduction of the analgesic response to a test dose of morphine (cross-tolerance) and moderate reduction of N-demethylation of morphine by liver enzyme preparations from rats occur when nalorphine and normorphine are given chronically. The in vitro N-dealkylation of nalorphine is not affected significantly. More than one enzyme seems to be involved in the N-dealkylation of narcotic drugs. The degree of tolerance, cross-tolerance and depression of enzymatic activity depends on the amount of drug given per day rather than on the duration of drug administration. Based on the observed parallelism of depression of enzyme activity and of analgesic response, the N-demethylating enzyme is proposed as a model for the study of narcotic-drug receptor sites.