CHANGES IN MORPHINE- AND CHLORPROMAZINE- N-DEMETHYLASE DURING THE DEVELOPMENT OF TOLERANCE TO CHLORPROMAZINE IN MICE

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Abstract
The development of tolerance to dihydromorphinone in mice could be prevented by treatment with chlorpromazine. Under certain conditions analgesic tolerance resulted from treatment with chlorpromazine alone. There was a two-to three-fold increase in the activity of dihydromorphinone-N-demethylase and chlorpromazine-N-demethylase in the livers of mice treated with chlorpromazine. The increase in chlorpromazine-N-demethylase was more rapid in mice kept at 33° than in mice kept at 22°, presumably because chlorpromazine-produced hypothermia interfered with protein synthesis in the liver. Mice showed tolerance to the hypothermic effect of chlorpromazine within 1 or 2 days. Tolerance was not related to increased metabolism of chlorpromazine. Treatment with ethionine blocked the chlorpromazine-induced increase in N-demethylase but did not prevent the development of tolerance. Tolerance developed more slowly at 33° than at 22°.