OPIOID PEPTIDE ANALOG FETAL EFFECTS

PPG这一部分的长期目标是评估 阿片肽类似物对心肺功能的药效学作用 胎儿的神经行为、神经内分泌和代谢功能。这个 该项目最初五年的具体目标将集中在 三个方面：1)定义胎儿对母体的反应 阿片肽类似物的给药具有高度的选择性 要么是Mu受体，要么是Delta受体。结果参数将包括 胎儿心率和心率变异性，呼吸运动，脑电， 血糖和乳酸水平以及几种应激状态下的血浆水平 激素(ACTH、皮质醇、催乳素和β-内啡肽)；2)至 确定胎盘药物转运对这些指标的贡献 直接给药这些多肽的药效学作用 与胎儿相似；以及3)确认这些受体的选择性 使用选择性MU和Delta拮抗剂的药效学作用。 拟议的研究将检验PPG的第二个一般假设， 也就是说，选择三角洲的激动剂对 对胎儿比MU-选择性激动剂。长期留置导管， 胎儿的EEG、EKG和横隔肌电极图 将允许连续记录胎儿血压、心率、脑电 以及清醒、无拘无束的动物的呼吸运动。连载 将采集胎儿血液样本进行葡萄糖、乳酸盐分析 以及荷尔蒙水平。将给予选择性MU和Delta激动剂 静脉注射(Iv)给母亲。对于那些多肽类似物来说 显著的胎盘转移，他们也将被静脉注射到 以确定其对胎儿的直接作用。受体 胎儿反应的选择性将通过使用 选择性的MU和三角洲拮抗剂。 连同James Clapp博士在组件4a中获得的结果， 这些数据将提供有价值的生理学理解。 阿片类药物对胎儿产生不良影响的机制。 此外，这些数据将有助于识别一组合成阿片类药物 其结构提供适当受体选择性的化合物 以及推荐他们作为安全候选药物的药效学行为 在人类妊娠中的急性和慢性使用。

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.