Infusion of Morphine in Maternal Rats at Near‐Term: Maternal and Foetal Distribution and Effects on Analgesia, Brain DNA, RNA and Protein

Abstract:Time‐dated pregnant (day 21–22) Sprague‐Dawley rats were infused intravenously with morphine 5 mg/kg per hr for periods up to 4 hrs. The blood, brain and placenta of maternal rats and the blood and brain of foetuses were collected and analyzed for morphine content. The morphine concentration in the blood of maternal and foetal rats was maximal after infusions for 3 hrs; at the maximum, the maternal concentration was 2800 ng/ml and the foetal concentration was 1900 ng/ml. The morphine levels of the brain were also maximal at 3 hrs. The foetal level, 2200 ng/g, was not significantly (P > 0.05) different from that of foetal blood, whereas the maternal brain level, 600 ng/g, was less than one‐fourth of the maternal blood level. The highest concentration of morphine in the placenta, 6200 ng/g, was also attained after infusion for 3 hrs. These data indicate that the placenta acts as a barrier to the passage of morphine from the maternal animal to the foetus and that a blood brain barrier to morphine exists in the adult but not in the foetal rat. Similar studies showed that an effective blood brain barrier is not present in 20 day old rats. Tolerance to the analgesic effect of morphine, 10 mg/kg subcutaneously, was demonstrated in non‐pregnant adult female rats 2 to 3 days following infusion of morphine, 5 mg/kg per hr for 4 hrs. Reaction times to a nocioceptive stimulus were thus significantly reduced at 1 hr after the test dose (from 19.6 sec. ±2.9 S.E.M. in untreated control animals to 6.8 sec. ±0.4 S.E.M. in the morphine infused animals). The saline infused rats had reaction times after the injection of morphine which did not differ significantly from the untreated control rats. Approximately 20 days after the infusion of morphine to day 21–22 pregnant rats the reaction times to a test dose of morphine were no longer significantly different from those of control rats given the test dose of morphine. The offspring of morphine infused rats were then tested for analgesic response to morphine, 0.45 mg/kg subcutaneously, at approximately 12 days of age and compared with offspring of saline infused rats. The reaction times for offspring of the morphine infused rats 1 hr after the test dose of morphine (26.2 sec. ±1.1 S.E.M.) were significantly greater than those of the offspring of saline infused rats (20.9 sec. ±1.5 S.E.M.). A rapid method for preparing isolated nuclei from adult and foetal rat brain in high yield, using detergent treatment and a onestep centrifugation on a discontinuous sucrose gradient, is described. DNA, RNA and protein content the maternal or the foetal brains, it is still possible that morphine could selectively alter RNA and protein synthesis in the brain without causing a significant change in the overall content of either RNA or protein in acute experiments.