Long-term objectives are (1) to test in a neonatal animal model whether prenatal cocaine enhances respiratory and sleep disturbances as a correlate of clinical reports on increased incidence of apnea, delayed arousal during hypoxia and Sudden Infant Death Syndrome (SIDS) in such cocaine-exposed infants, and (2) to explore whether suppressant neuromodulatory systems, such as opioids, might play a role as a mechanism in this pathophysiology. If so, this research may lead to therapeutic modalities, directed at the opioid systems, which will benefit infants of cocaine abusing mothers.
Specific aims are (1) to expose pregnant sows to cocaine throughout the third trimester; (2) to employ our established neonatal piglet model, the physiology and maturational pattern of which appear to simulate those of the human infant. Three age groups of unexposed vs. cocaine exposed piglets will be studied: 1-3 days old to assess withdrawal from prenatal cocaine exposure, and 4-11 as well as 25-35 days old, representing an immature and a more mature respiratory control, to assess long-term effects of prenatal cocaine exposure; (3) to assess whether prenatal cocaine exposure perturbs cardiorespiration, sleep or behavior; (4) to test whether any such abnormality is reversed with opioid antagonism, and (5) to establish whether prenatal cocaine exposure is associated with an abnormal content or release of opioids or with a change in opioid receptors in crucial brain regions. Specifically, in 4-11 and 25-35 day old chronically instrumented piglets, central respiratory neuronal activity from the ventral respiratory group (nucleus ambiguus and adjacent structures), diaphragm and upper airway muscle activity, arterial gas tensions, pH and pressure, heart rate and sleep/wake states will be assessed during normoxia and hypoxia, with and without mu, delta and kappa antagonists. Spontaneous behavior will be quantified in uninstrumented piglets of all age groups as well as in the chronically instrumented piglets before and after opioid antagonists. In 4-11 and 25-35 day old piglets, opioid proopiomelanocortin products (beta-lipoprotein, beta-endorphin, the active peptide, and N-acetyl(beta)-endorphin), methionine-enkephalin and dynorphin 1-13 will be measured by radioimmunoassay in micropunched and microdialyzed respiratory and arousal-related brain regions as well as in cerebrospinal fluid and plasma. Mu, delta and kappa opioid receptors will also be quantified by autoradiography in the same brain regions.
