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

Abstract

Summary1. 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 "4C-lysine into rat brain protein, and "4C-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 ug/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 ,ug/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 ,ug/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.

Tolerance to Morphine‐induced Calcium Depletion in Regional Brain Areas: Characterization With Reserpine and Protein Synthesis Inhibitors

“…Therefore, it might be reasoned that the induction of tolerance to the depletion of calcium may in some way be connected to the translational aspect of protein synthesis. In support of this reasoning, Datta & Antopol (1973) Krivoy & Ungar, 1965;Loh, Shen & Way, 1969;Cox & Osman, 1970;Feinberg & Cochin, 1972). Our data confirm these observations with cycloheximide and also support the lack of effects of chloramphenicol on tolerance development previously reported by Cox & Osman (1970).…”

Role of 5‐hydroxytryptamine in ketamine‐induced hypothermia in the rat

“…Ketamine was injected intraperitoneally in graded doses ranging between 20 and 100 mg/kg. It was also injected intracerebrally as described by Cox & Osman (1970) in a dose of 0 5 mg/rat contained in 50 ,u with a sterile tuberculine syringe. The site of injection was within 5 mm of either side of the midline on a line drawn through the anterior base of the ears.…”

The Offset of Morphine Tolerance in Rats and Mice

“…A difficulty in measuring the level of morphine tolerance arises from the fact that the test procedure necessarily involves the administration of an opioid analgesic which then reinforces the phenomenon being measured. This problem has been circumvented in the present experiments by the simultaneous administration of a protein synthesis inhibitor with the test dose of opioid drug, a procedure which prevents the further development of tolerance whilst not affecting previously established tolerance (Cox, Ginsburg & Osman, 1968; Cox & Osman, 1970). A preliminary account of this work has been presented to a meeting of the British Pharmacological Society (Cox, Ginsburg & Willis, 1973).…”