The purpose of this proposal is to study the role of endorphins in ventilatory and cardiovascular control at rest and during stress (e.g. hypoxia) as a function of age and state of consciousness in unanesthetized chronically instrumented puppies and adult dogs. On the basis of our previous work, we hypothesize that various opiate receptor subtypes have different roles in cardiorespiratory control and that these roles depend on age in early life. We intend to 1) study the role of delta-, mu- and Kappa-receptors in cardiorespiratory function with maturation and 2) study the cardiorespiratory responses to moderate and severe hypoxia and determine whether these responses are mediated by the opiate receptor subtypes under consideration. Because it has been shown that morphine-like substances are enzymatic digests of B-casein, we will study the relation of milk intake to changes in plasma B-casomorphin and morphiceptin. We will measure ventilation by the barometric method, heart rate and heart rate variability using an accurate pre-processor, cardiac output using the Fick principle and 02 consumption in a closed system in puppies and dogs. Sleep will be staged using EEG, EOG and behavioral criteria. Chronic cannulae, implanted over the cisterna magna or in cerebral ventricles, will be used for sampling CSF or for injection of agonists or antagonists. Total CSF opiates will be assayed during normoxia and hypoxia and plasma and CSF morphiceptin and B-casomorphin levels will be measured after milk intake using radioimmunoassays. Autoradiographic techniques will localize receptor-agonist interaction. We believe that it is only with an understanding of the biochemical basis of defects such as hypoventilation, apnea and cardiovascular instability in the young during wakefulness and sleep that it is possible to develop new approaches to treatment of a variety of pediatric illnesses including apnea of prematurity and upper airway obstruction. This proposal is particularly relevant to the understanding of the pathogenesis of Sudden Infant Death Syndrome since this proposal is very likely to generate new and important data regarding the relation of the state of consciousness, cardiorespiratory control and 02 consumption to blood and CSF endorphin levels after milk feeding.
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