Inhibition of the development of tolerance to morphine in rats by drugs which inhibit ribonucleic acid or protein synthesis.

1. A study has been made of the effects of a number of drugs which have as a common property the ability to inhibit RNA or protein synthesis, on the development of tolerance to the analgesic effects of morphine, given by intravenous infusion, in rats.2. Measurements were also made of the effects of the drugs on the incorporation of (14)C-lysine into rat brain protein, and (14)C-orotic acid into rat brain RNA.3. Actinomycin D, 6-mercaptopurine and 5-fluorouracil reduced the acquisition of tolerance to morphine at doses which also produced significant inhibition of incorporation of orotic acid into brain RNA. Tolerance development was only affected by 6-mercaptopurine and 5-fluorouracil after intracerebral administration.4. 6-Mercaptopurine and 5-fluorouracil did not significantly affect the incorporation of lysine into protein, although a small but significant reduction in lysine incorporation was produced by infusion of actinomycin D at 20 mug/kg per hr.5. Development of tolerance to the analgesic effects of morphine was also reduced by cycloheximide and puromycin. These drugs markedly reduced the incorporation of lysine into brain protein. Puromycin and low doses of cycloheximide (50 mug/kg per hr) did not significantly affect RNA synthesis as measured by orotic acid incorporation, but RNA synthesis was clearly reduced by administration of cycloheximide at 200 mug/kg per hr.6. These results support the hypothesis that the synthesis of new RNA and protein in the brain is an essential feature of the development of tolerance to morphine in rats.