Prenatal morphine exposure and sleep-wake disturbances in the fetus

We have previously shown that acute exposure to low-dose morphine stimulates arousal and breathing movements in the fetal lamb. We now report on the effects of subacute low-dose morphine exposure on the regulation of fetal sleep-wake behavior and breathing patterns. Morphine was infused to 11 fetal lambs (121-129 days gestation) at a constant rate of 400 micrograms/h for 7 days via a mini osmotic pump implanted subcutaneously in the maternal flank and connected directly to an indwelling catheter in the fetal vena cava. On day 1, morphine resulted in a state of arousal in all fetuses, with loss of quiet sleep and rapid eye movement (REM) sleep. This response was greatly reduced by day 2 and was insignificant by day 3, despite continuous drug exposure. There was no decrease in plasma morphine levels. Two fetuses died during morphine exposure. Upon removal of the pump, all fetuses exhibited disturbances in their sleep cycles within 1-3 h, with an increase in arousal time and loss of REM sleep. The duration of the arousal and quiet sleep episodes was also greatly reduced. Such disturbances were noted for 3-4 days after termination of morphine infusion. Four fetuses were delivered prematurely (131-136 days) during this period. These results demonstrate the rapid onset of tolerance to low-dose morphine exposure in the fetus and the development of physical dependence, as manifested by a mild abstinence syndrome characterized by sleep-wake disturbances.