Effects of prenatally-administered morphine on brain development and resultant tolerance to the analgesic effect of morphine in offspring of morphine treated rats.

: Timed-pregnant Sprague-Dawley rats were injected subcutaneously with morphine 20 mg/kg on gestational days 17–20 or infused intravenously with morphine 5 mg/kg for 4 hrs on gestational day 21 or 22. They were then allowed to litter normally except when studied at 1 hr after birth. The body weight, brain weight, total brain DNA, RNA and protein and the incorporation of labelled thymidine, uridine and amino acids into corresponding brain macro-molecules of young of morphine treated and control rats were measured at the age of 1 hr and 1, 2, 12, 13, 20, 26 and 32 days after birth. Separate groups of young were tested for analgesic response to morphine using a nocioceptive (55$dG surface) stimulus. Offspring of morphine injected mothers exhibited significant reduction in body weight at every age level, except at 26 days. The reduced body weight was paralleled by reduced brain weights up to the age of 12 days. The values for brain weight expressed as a percentage of body weight were significantly higher for the morphine than the control young in every age group even though the brain weights of the morphine young in the three oldest groups were the same or higher than those of controls. It was concluded that the brain is less affected than the body as a whole. The lower brain weights of the 1, 2 and 12 day old morphine offspring were paralleled by consistently lower total amounts of brain DNA, RNA and protein. RNA/DNA and protein/DNA ratios in brain thus remained unchanged. The decreased macromolecular contents in the morphine young were in general paralleled by decreased incorporation of radioactive precursors into brain macromolecules up to the age of 12 days. It was concluded that suppression of macromolecular synthesis and growth retardation in brain resulted from suppressed cell division. Offspring of morphine infused mothers exhibited no significant difference in weight at birth, brain weight, and total amounts of DNA, RNA and protein in the brain. It was, however, found that incorporation of labelled precursors tended to be lower in the brain of the morphine young at birth and at one day and that body weights were significantly less at the age of 12–13 days whereas incorporation into brain macromolecules was significantly higher than that in the control young at 13 days. The results were interpreted in terms of a rebound phenomenon which followed an inhibitory effect of morphine on cell division in the brain. Offspring of morphine injected mothers exhibited a pronounced rebound elevation of brain weight and macromolecular contents but not incorporation at the age of 20 days. After 20 days these differences levelled out, except for total RNA which was found to be significantly greater in 26 day old morphine offspring. Analgesic experiments with young of morphine injected mothers showed that tolerance to morphine analgesia, except for decreased duration of analgesia, disappeared between 12 to 20 days of age, whereas experiments with 12 to 13 day old young of morphine infused mothers showed that the analgesic action of morphine was significantly greater in the morphine than in the control young. The above results of morphine analgesia can best be explained by the hypothesis that tolerance to morphine analgesia is characterized by suppressed cell division and reduced macromolecular synthesis in brain, and different stages of recovery from these effects of morphine in the brain are associated with differences in sensitivity to morphine analgesia, i. e. ongoing recovery with high sensitivity and complete recovery with normal sensitivity.