The overall goal of this project is to determine the mechanisms of action of morphine on neurobehavioral, respiratory and cardiovascular activity in the developing fetus. Furthermore, we wish to explore possible reasons for the difference in morphine's effects in the fetus and the adult. All proposed studies are to be carried out using the chronic fetal lamb model.
The specific aims are: 1) to determine if the excitatory and depressant effects of morphine are mediated by central or peripheral opioid mechanisms. This will be accomplished using a quartenary opiate antagonist that does not cross the blood brain barrier. 2) to determine if the stimulation of neurobehavior and cardiorespiratory activities by low doses or morphine are mediated by catecholamine release and hyperglycemia, and if so, to determine the mechanisms of the catecholamine response. This will be demonstrated by measuring plasma norepinephrine, epinephrine and dopamine levels, and glucose levels; and comparison or morphine's effects in 4 treatment groups: guanethidine pretreatment, hexamethonium pretreatment, adrenal denervation and adrenal demedullation. 3) to determine if the dual actions of morphine are mediated by different opiate receptor subtypes. This will be demonstrated in 2 ways: the use of agonists selective for the mu, delta and kappa receptors; and the administration iof morphine in the presence of selective antagonists for the mu, mu1, delta and kappa receptors. 4) to determine if the endogenous opioid peptides exhibit similar pharmacologic profiles. We propose to compare the effects of Met-enkephalin, b-endorphin and hynorphin with those of morphine and the more selective anonists. 5) to determine if the differences between morphine's action in the fetus and adult may be due to differenes in the proportions of the various subtypes of opiate receptors. Mu1, mu2, delta and kappa binding will be determined in whole brain and adrenal homogenates from mother and fetus at various gestational ages. Regional cerebral localization of the binding sites will be determined using in vitro autoradiography. 6) to determine if the more pronounced excitatory action of morphine in the fetus may be due to differences in the proportion of enkephalin peptides to catecholamines in the fetal adrenal medulla. Enkephalin peptides and catecholamines will be measured in homogenates of fetal adrenal medulla at various gestational ages and compared to levels in adult adrenal medulla.
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