OPIOID PEPTIDE ANALOG FETAL EFFECTS

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The long-range goal of this portion of the PPG is to evaluate the pharmacodynamic effects of opioid peptide analogs on cardiorespiratory, neurobehavioral, neuroendocrine and metabolic function in the fetus. The specific aims for the initial five years of the project will focus in three areas: 1) to define the fetal response profile to maternal administration of opioid peptide analogs which are highly selective for either the mu or delta receptor. The outcome parameters will include fetal heart rate and heart rate variability, breathing movements, EEG, plasma glucose and lactate levels, and plasma levels of several stress hormones (ACTH), cortisol, prolactin and Beta-endorphin); 2) to determine the contribution of placental drug transfer to these pharmacodynamic actions by direct administration of these peptide analogs to the fetus; and 3) to confirm the receptor selectivity of these pharmacodynamic actions using selective mu and delta antagonists. The proposed studies will test the second general hypothesis of the PPG, namely that delta-selective agonists will have fewer adverse effects on the fetus than mu-selective agonists. Chronic indwelling catheters, together with EEG, EKG, and diaphragmatic EMG electrodes, in the fetus will permit continuous recording of fetal blood pressure, heart rate, EEG and breathing movements in a conscious, unrestrained animal. Serial fetal blood samples will be collected for analysis of glucose, lactate and hormone levels. Selective mu and delta agonists will be administered intravenously (iv) to the mother. For those peptide analogs that show significant placental transfer, they will also be administered iv to the fetus to determine their direct actions on the fetus. Receptor selectivity of the fetal responses will be demonstrated with the use of selective mu and delta antagonists. Together with the results obtained by Dr. James Clapp in Component 4a, these data will provide valuable understanding of the physiological mechanisms which underlie the adverse effects of opioids on the fetus. In addition, these data will serve to identify a set of synthetic opioid compounds whose structure provide the appropriate receptor selectivity and pharmacodynamic actions to recommend them as candidates for safe acute and chronic use in human pregnancy.