The long-term objective of this competitive application is to continue our investigation of the postnatal maturation of respiratory pattern and control and their possible modulation by the opioid system. The experimental model for this research is the piglet, the physiology and maturational pattern of which appear to simulate those of the human infant. Two age groups will be studied: 1-10 days old, whose respiratory control is immature, and 21-30 days old, who are more mature in this respect. Specifically, opioid proopiomelanocortin products (beta-lipotropin, beta-endorphin, the active peptide, and N-aceytl beta-endorphin), methionine-enkephalin and dynorphin(1-13) will be measured by radioimmunoassay following separation by high pressure liquid chromatography in micropunched and microdialyzed respiratory-related regions in the brain stem, as well as in plasma and cerebrospinal fluid during normoxia and hypoxia.
The aim here is to assess the baseline content of these peptides and their possible increased release during hypoxia. Except for the microdialysis experiments, no anaesthesia will be employed. The second major experimental approach will comprise physiological measurements of central respiratory-related unit activities (at the ventral and dorsal respiratory groups) and peripheral respiratory (diaphragmatic, posterior cricoarytenoid) muscle functions in relation to arterial pH/gas tensions, sleep/wake states, blood pressure and heart rate during normoxia and hypoxia. These will serve to assess the effect of specific agonists, antagonists and ligand-specific antisera on each of the three opioid receptors (mu, delta, k), and ligands on the individual and interactive functions of these components on respiratory control during development. Except for a preliminary set of acute experiments to characterize central respiratory units, all experiments will be conducted in chronically instrumented, behaving piglets. It is hoped that this research will shed additional light on normal and abnormal maturational processes of respiratory pattern and control in the human infant, on the possible role of the opioid system in the pathophysiological dysrhythmia of breathing, and on possible therapeutic interventions.
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