MORPHINE-6-GLUCURONIDE--DEVELOPMENT OF BREATHING CONTROL

本提案的目标是确定以下问题的程度和后果 豚鼠胎儿和新生儿暴露于吗啡-6-葡萄糖醛酸脂的研究 (M6G)，吗啡和海洛因的活性代谢物。M6G将成为 在胎儿和母体组织中的高效定量 慢性接触吗啡后的液体色谱检查。母体、胎儿和 将在肝微粒体中检测MOR产生的新生儿M6G 准备工作。宫内慢性MOR暴露对新生儿的影响 呼吸、氧气消耗和二氧化碳产生将是 使用非侵入性体积描记技术进行研究。新生儿生长发育 将会受到监控。剂量、血浆和脑内药物的相互关系 将在#年检查呼吸抑制的浓度和强度 新生儿作为年龄的函数。吗啡-3-葡萄糖醛酸苷的呼吸效应 (M3G)，海洛因和吗啡的代谢物，其活性与 M6G，以及它从MOR形成的程度将被研究和 与M6G相比。阿片受体拮抗剂纳洛酮的作用 将M6G的反转呼吸抑制与 假想的M3G的拮抗作用。豚鼠是一种合适的 M6G在几个方面的人类围产期药理模型： 豚鼠产生MOR的葡萄糖醛酸代谢物；呼吸 对麻醉药品和二氧化碳的反应在两者中是相似的 豚鼠的血膜胎盘类似于 人体胎盘的结构和渗透性特征。这个 M6G的重要性直到最近才被认识到，因此其 胎儿和新生儿的药理几乎是未知的。由于滥用 麻醉药品，如海洛因和吗啡，在怀孕期间是一种实质性的 美国的公共卫生问题，以及在子宫内暴露于这些物质 毒品被认为与呼吸异常有关，并增加了 婴儿猝死综合征(SIDS)的发病率，重要的是 了解可能积聚的活性代谢物的药理作用 在怀孕期间。这项研究的数据将在 研究海洛因和吗啡的活性代谢物是否在 新生儿呼吸异常的发展，其中一些可能 为小岛屿发展中国家、教育育龄妇女和关怀作出贡献 适用于在宫内接触过麻醉剂的婴儿。

The goal of this proposal is to determine the extent and consequence of exposure of the guinea pig fetus and neonate to morphine-6-glucuronide (M6G), an active metabolite of morphine (MOR) and heroin. M6G will be quantitated in fetal and maternal tissues by high-performance liquidchrnmatography after chronic exposure to MOR. Maternal, fetal and neonatal production of M6G from MOR will be examined in hepatic microsomal preparations. The effect of chronic in utero MOR exposure upon neonatal breathing, oxygen consumption and carbon dioxide production will be studied using a noninvasive plethysmographic technique. Neonatal growth will be monitored. The interrelationship of dose, plasma and brain drug concentrations and intensity of respiratory depression will be examined in neonates as a function of age. Breathing effects of morphine-3-glucuronide (M3G), a metabolite of heroin and MOR with activities opposite to those of M6G, and the extent of its formation from MOR will be examined and compared to M6G. Ability of the opiate receptor antagonist naloxone to reverse the breathing depression of M6G will be compared to the hypothesized antagonistic effects of M3G. The guinea pig is an appropriate model for the human perinatal pharmacology of M6G in several respects: the guinea pig produces the glucuronide metabolites of MOR; the breathing response to narcotic drugs and carbon dioxide is similar in the two species; and the guinea pig has a hemomonochorial placenta similar in structure and permeability characteristics to the human placenta. The importance of M6G has only been recognized recently and therefore its fetal and neonatal pharmacology is virtually unknown. Since abuse of narcotic drugs, such as heroin and MOR, during pregnancy is a substantial public health problem in the United States, and in utero exposure to these drugs has been implicated in breathing abnormalities and in an increased incidence of the sudden-infant-death syndrome (SIDS), it is important to understand the pharmacology of active metabolites which may accumulate during pregnancy. The data from this research will be valuable in investigating whether active metabolites of heroin and MOR have a role in the development of neonatal breathing abnormalities some of which may contribute to SIDS, in educating women of child bearing age, and in caring for infants who have had in utero narcotic exposure.