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°.
Mice became tolerant within a few days to the analgesic and exciting effects of narcotics as a result of drinking dilute evaporated milk containing dihydromorphinone HCl (Dilaudid). Tolerant mice could be maintained in good physical condition for 1 month or more while drinking between 50 and 70 mg per kg of dihydro-morphinone HCl daily.
When tolerant mice were withdrawn they lost as much as 15% of their body weight over-night, indicating that physical dependence was established.
The extent of tolerance increased with increasing daily intake of dihydromorphinone and with the length of time, up to about 7 days, that animals were maintained on one given dose.
Mice made tolerant by drinking dihydromorphinone showed decreased excitability. This was manifested by decreased spontaneous activity and a decreased response to the exciting effects of morphine, meperidine, codeine, cocaine, and, to a lesser extent, d -amphetamine. There was tolerance to the analgesic effects of morphine, meperidine and cocaine.
The assay, by means of a photoelectric counter, of motor activity following a test dose of narcotic is a sensitive and convenient method for measuring narcotic tolerance in mice.
