The long-term objectives of this research are to identify the pathophysiological mechanisms responsible for the respiratory and sleep-wake state perturbations possibly related to the increased incidence of Sudden Infant Death found in infants exposed prenatally to cocaine. This research uses a neonatal swine model, long established in our laboratory. We hypothesize that the activation of endogenous opioid systems is involved in these perturbations. This hypothesis is based on our previous work showing, first, that mu- and delta-opioid systems influence respiratory and sleep-wake patterns during early postnatal development in normal piglets, and second, that piglets exposed prenatally to cocaine display a delayed postnatal maturation in these physiological systems that is accompanied by an increased mu- and delta-opioid ligand content in central respiratory-related brain regions. Thus the present project is a natural extension of that work, aiming at a better definition of the relationship between prenatal cocaine, opioid function and respiratory/state behavior. The animal model comprises paired piglet litters, one of which is exposed to cocaine during 0.66 to 1.0 gestation, spanning the porcine prenatal spurt of brain growth and period of brain vulnerability. Physiological studies will assess the effects of mu- and delta-opioid antagonists on sleep-wake states and respiratory patterns and control in 6-10, 12-16 and 23-30 day-old, cocaine preexposed vs unexposed piglets. Cellular studies will map and quantify mu-and delta-opioid ligands and/or receptors and their messenger RNAs in respiratory- and sleep-wake-related brain regions of cocaine preexposed vs unexposed, 6, 12, and 23 day-old piglets, using quantitative autoradiography, immunocytochemistry and in situ hybridization. A demonstration of enhanced opioid activation in cocaine preexposed vs unexposed human neonates will provide insights on possible therapeutic or preventive measures for cocaine-preexposed human infants.
