Abstract

After 0.5 mg/kg i.p. of dactinomycin (actinomycin D, Cosmegen) the s.c. LD50 of morphine in mature mice was 460 mg/kg whereas without dactinomycin it was 800 mg/kg. Estimation of brain concentrations of morphine indicated that the levels of morphine in dactinomycin-treated animals were appreciably higher than those in nontreated animals. Two hours after morphine administration dactinomycin-treated animals exhibited a mean brain level of morphine approximately twice that of the control group. In immature mice which had not developed a blood-brain barrier to morphine, dactinomycin did not alter the LD50 of morphine nor the distribution of morphine in the brain. Dactinomycin also did not influence the lethality of heroin in adult mice. In the adult rat, dactinomycin also enhanced brain uptake of morphine. After treatment with dactinomycin, a higher brain/blood ratio of morphine was obtained without any alteration in the plasma binding of morphine. It appears, therefore, that dactinomycin enhances toxicity to morphine at least in part by increasing brain permeability to morphine.