The discovery of multiple classes of opiate receptors has led to the hypothesis that the diverse actions of opiates may be mediated by different opiate receptors. Available data suggest different, and even opposing, roles for the various receptor subtypes in analgesia, cardiorespiratory, neuroendocrine and metabolic regulation. Studies on the ontogeny of the receptor subtypes have revealed different rates of development for the mu, delta and kappa binding sites in several animal species, resulting in varying proportions of the different binding sites as a function of age. However, the functional implications of the differential ontogeny of these receptor subtypes remain unclear. The primary objective of this proposal is to determine the functional roles of opiate receptor subtypes in early development in the fetal lamb. In this proposal, it is hypothesized that: 1) the mu, delta and kappa receptors mediate different actions on fetal neurobehavioral, cardiorespiratory, neuroendocrine and metabolic regulation; 2) the functional responses to mu, delta and kappa receptor activation change as a function of gestational age; 3) the endogenous opioid peptides exert tonic influence at the various receptor subtypes to modulate neurobehavioral, cardiorespiratory, neuroendocrine and metabolic function. Recent work from our laboratory have already shown that mu and delta receptors exert different actions on neurobehavioral and cardiorespiratory functions in the late-term fetal lamb.
Our specific aims for the next 5 years are as follows: 1) extend these studies to investigate the effects of kappa agonists on fetal EEG, breathing movements, blood pressure and heart rate; 2) determine the effects of selective mu, delta and kappa agonists on plasma ACTH, cortisol, prolactin, growth hormone and vasopressin levels; 3) determine the effects of mu, delta and kappa agonists on blood glucose and lactate levels; 4) compare the response profiles to selective mu, delta and kappa agonists at two gestational ages (100-115d and 125-140d); and 5) ascertain the functional roles of the endogenous opioid peptides by using selective mu, delta and kappa antagonists. The overall experimental plan will include: use of a conscious unanesthetized animal model, examination of multiple pharmacologic functions, incorporation of two gestational age groups, use of highly selective opiate agonists and antagonists, complete dose-response design with vehicle control, and demonstration of response blockade by selective antagonists. The proposed studies will provide new information on the functional roles of opiate receptor subtypes in the fetus, and should be helpful in the design of better analgesics for perinatal use.
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