MORPHINE-6-GLUCURONIDE--DEVELOPMENT OF BREATHING CONTROL

吗啡-6-葡萄糖苷酸--呼吸控制的发展

• 批准号: 2120342
• 负责人: GEORGE D OLSEN
• 金额: $ 16.95万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-15 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2120342
• 关键词: brain metabolism; carbon dioxide; computer data analysis; drug abuse; embryo /fetus; growth /development; guinea pigs; heroin; high performance liquid chromatography; infant animal; liver metabolism; microsomes; morphine; naloxone; oxygen consumption; perinatal; plethysmography; pregnancy; respiratory disorder; sudden infant death syndrome; toxin metabolism

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.

该提议的目的是确定 豚鼠胎儿和新生儿暴露于吗啡-6-葡萄糖醛酸苷 （M6G），一种活跃的吗啡（MOR）和海洛因的代谢物。 M6G会 通过高性能在胎儿和母体组织中进行定量 长期暴露于MOR后的液体chrnmatography。母亲，胎儿和 MOR的新生儿产生将在肝微粒体中检查 准备。慢性在子宫内部暴露对新生儿的影响 呼吸，氧气消耗和二氧化碳的产生将是 使用非侵入性整数学技术进行了研究。新生儿生长 将受到监视。剂量，血浆和脑药物的相互关系 将检查呼吸抑郁的浓度和强度 新生儿与年龄的关系。吗啡-3-葡萄糖醛酸的呼吸作用 （M3G），一种海洛因和MOR的代谢物，活动与活动相反 M6G及其由MOR的形成程度将被检查，并且 与M6G相比。鸦片受体拮抗剂纳洛酮的能力 将M6G的呼吸抑制扭转与 M3G的假设拮抗作用。豚鼠是合适的 M6G人类围产期药理学的模型多个方面： 豚鼠产生MOR的葡萄糖醛酸代谢物；呼吸 对麻醉药物和二氧化碳的反应在两者中相似 物种;豚鼠的血液学胎盘相似 人胎盘的结构和渗透率。这 M6G的重要性最近才被确认，因此 胎儿和新生儿药理学实际上是未知的。自滥用以来 麻醉药物（例如海洛因和MOR）在怀孕期间是一个实质性的 美国的公共卫生问题以及子宫暴露于这些问题 药物与呼吸异常有关，并增加 突然 - 死亡综合征（SIDS）的发生率，重要的是 了解可能积累的活性代谢物的药理学 怀孕期间。这项研究的数据在 调查海洛因和MOR的主动代谢产物是否在 新生儿呼吸异常的发展可能 为小岛屿发展中国家，教育儿童养育年龄的妇女和关怀做出贡献 对于在子宫麻醉剂暴露中曾经有过的婴儿。