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: 6137791
• 负责人: GEORGE D OLSEN
• 金额: $ 18.43万
• 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 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6137791
• 关键词: apnea; behavioral /social science research tag; brain stem; chronic disease /disorder; developmental neurobiology; drug abuse; drug metabolism; embryo /fetus toxicology; glucuronides; guanosine triphosphate; guinea pigs; morphine; neuropharmacology; newborn animals; opioid receptor; pharmacokinetics; receptor binding; receptor expression; respiration regulatory center; respiratory pharmacology; tissue /cell culture

The overall goal of this research is to examine the development of mu opioid receptors in the brainstem of the neonatal guinea pig in order to better understand the respiratory effects of chronic in utero morphine exposure and the role of morphine's active metabolite, morphine-6-beta-D-glucuronide (M6G), in respiratory depression. There are three main aspects to this proposal on the study of the mu opioid receptor that, when combined, make it unique. They are: 1) location, with the emphasis on the respiratory nuclei of the brainstem; 2) development, with the emphasis on the neonatal animal during the first week after birth; and 3) treatment, with the emphasis on chronic intermittent versus a constant rate of in utero morphine exposure. The anatomical studies include the localization and quantitation of mu opioid receptors and receptor mRNA using immunohistochemistry, autoradiography, in situ hybridization and reverse transcriptase polymerase chain reaction (RT-PCR); the pharmacological studies include characterization of binding profiles of brainstem membranes and stably transfected CHO cells; and the functional studies include the determination of opioid-induced GTPgammaS binding in tissue and cells. These studies will provide new information about the role of mu receptors in development, morphine-induced respiratory depression, and importantly, the relationship of M6G binding (to mu and to a potential atypical site) in morphine-induced respiratory effects. The hypotheses are: 1) that there are developmental changes in D- Ala2-MePhe4-Gly-ol5-enkephalin (DAMGO) binding and opioid-induced GTPgammaS binding in brainstem respiratory nuclei during the first week of life; 2) that developmental changes in the mu opioid receptor are affected by in utero morphine exposure; and 3) that there are quantitative and qualitative differences between [3H]-DAMGO and [3H]-M6G binding and opioid-induced GTPgammaS binding in the brainstem during postnatal development and following in utero morphine exposure. Changes in opioid receptors associated with respiratory nuclei have consequences for the effects of morphine and M6G on breathing. This study is of significance for the fetus and neonate who are exposed in utero to heroin or other opioids because of maternal drug abuse, maintenance therapy of pregnant former opioid abusers or pain therapy.

这项研究的总体目的是检查新生儿豚鼠脑干中MU阿片受体的发展，以便更好地了解慢性吗啡接触子宫内吗啡的呼吸作用以及吗啡活性代谢物，Omphine-6-6-beta-d-beta-d-beta-d-beta-d-d-beta-d-d-d-d-葡萄糖苷（M6G）。 该提案在研究MU阿片受体的研究方面有三个主要方面，当结合使用时，它使其独一无二。 它们是：1）位置，重点是脑干的呼吸核； 2）发展，重点是出生后的第一周新生儿动物； 3）治疗，重点是慢性间歇性与子宫内吗啡暴露的恒定速率。解剖学研究包括使用免疫组织化学，放射自显影，原位杂交和逆转录酶聚合酶链反应（RT-PCR）对MU阿片受体和受体mRNA的定位和定位；药理研究包括表征脑干膜的结合谱和稳定转染的CHO细胞的表征；功能研究包括确定组织和细胞中阿片类药物诱导的GTPGAMMAS结合。 这些研究将提供有关MU受体在发育，吗啡诱导的呼吸道抑郁症的作用的新信息，以及重要的是，M6G结合（与MU和潜在的非典型部位）在吗啡诱导的呼吸作用中的关系。假设是：1）在生命的第一周，D-Ala2-Mephe4-Gly-Gly-Gly-Gly-ol5-源石（DAMGO）结合和阿片类药物诱导的GTPGAMMAS结合的发育变化； 2）在子宫内吗啡暴露中，MU阿片受体的发育变化受到影响； 3）[3H] -DAMGO和[3H] -M6G结合和阿片类药物诱导的GTPGAMMAS在产后发育过程中的脑干结合和子宫内吗啡暴露中，存在定量和定性差异。与呼吸核相关的阿片受体的变化对吗啡和M6G对呼吸的影响有影响。 这项研究对于因母体药物滥用，孕妇的前阿片类药物滥用者或疼痛治疗而在子宫内暴露于海洛因或其他阿片类药物的胎儿和新生儿具有重要意义。