Neonatal Morphine: Long-term Cerebrovascular Effects

描述（由申请人提供）：长期使用麻醉剂如吗啡来缓解危重早产儿的压力是一个重要的卫生保健问题——部分原因是产后环境对成人疾病的重要影响。大多数致力于麻醉品对发育中的大脑影响的研究都集中在它们的“神经毒性”作用上。然而，吗啡，最常用的新生儿麻醉剂，也有明显的脑血管作用。越来越多的证据表明，血管发育可以影响神经元祖细胞的命运，血管发育异常可能影响大脑发育和脑血管疾病的风险。因此，未成熟新生儿长期使用吗啡会影响大脑循环的发育和功能，而且这些影响可能是永久性的。目前还没有关于新生儿吗啡对脑循环发育的长期影响的研究。因此，本探索性拨款提案的目的是研究新生儿吗啡对脑血管的长期影响——对功能和解剖发育的影响。我们有初步的数据显示，成年大鼠（特别是雄性）在新生儿期暴露于吗啡后，其脑小动脉对腺苷的反应性发生了改变。在本提案中，我们将进一步表征这些脑血管效应，包括对血管生成的潜在影响，并将检查潜在的性别差异。我们还将探索吗啡对脑血管长期影响的潜在统一机制，验证新生儿吗啡上调脑内皮素ETA受体的假设，从而永久性地影响脑血管生成和改变血管反应性。有三个具体目的：1)使用离体脑小动脉制备，我们将进一步表征新生儿吗啡对成人脑血管反应性的影响，重点是腺苷药理学和血管生理学；2)利用免疫组织化学和体视学技术，研究新生儿吗啡对内皮细胞增殖和脑血管密度的局部影响；3)应用免疫组织化学和免疫印迹技术，观察新生儿吗啡对成年大鼠大脑中动脉内皮素受体表达和定位的影响。提高对新生儿吗啡暴露对脑血管的长期影响的了解，对临床医生护理危重早产儿以及幸存者的长期健康和福祉具有相当重要的意义。我们预计，这些探索性研究的结果将导致重要的未来研究，以检查吗啡对发育中的脑循环的影响的其他机制和后果。项目简介：关于我们在危重、非手术早产儿中增加使用吗啡的风险-收益比存在相当大的争议。目前尚不清楚长期使用这种强效药物对脑血管发育和晚年功能的长期影响。这些拟议的研究旨在开始填补这一重要领域的一些巨大知识空白。

DESCRIPTION (provided by applicant): Prolonged use of narcotics such as morphine to relieve stress in critically ill preterm infants is an important health care issue-- in part because of the important influence of the postnatal environment on adult diseases. The majority of studies devoted to the effects of narcotics on the developing brain have focused on their "neurotoxic" effects. However, morphine, the most commonly used neonatal narcotic, also has significant cerebrovascular effects. There is mounting evidence that developing blood vessels can influence the fate of neuronal progenitors and that abnormal vascular development may influence brain development and risk for cerebrovascular disease. Prolonged morphine use in immature neonates could thus affect both the development and function of the cerebral circulation, and these effects could be permanent. There have been no studies investigating the long-term effects of neonatal morphine on the developing cerebral circulation. The objective of this exploratory grant proposal is thus to examine the long-term cerebrovascular effects of neonatal morphine--effects on both function and anatomical development. We have preliminary data showing altered cerebral arteriolar reactivity to adenosine in adult rats (particularly, males) which were exposed to morphine in the neonatal period. In this proposal, we will further characterize these cerebrovascular effects, including potential effects on angiogenesis and we will examine potential gender differences. We will also explore one potential unifying mechanism for morphine's long-term cerebrovascular effects, testing the hypothesis that neonatal morphine up-regulates brain endothelin ETA receptors which in turn permanently affects cerebral angiogenesis and alters vessel reactivity. There are three specific aims: 1) Using an isolated cerebral arteriolar preparation, we will further characterize the effects of neonatal morphine on adult cerebrovascular reactivity, focusing on adenosine pharmacology and vessel physiology; 2) Using immunohistochemistry and stereology, we will examine the regional effects of neonatal morphine on endothelial cell proliferation and cerebral vessel density; and 3) Using immunohistochemistry and Western blotting, we will examine the effects of neonatal morphine on adult expression and localization of endothelin receptors in the middle cerebral artery. Improved understanding of the long-term cerebrovascular effects of significant neonatal morphine exposure is of considerable importance to clinicians caring for critically ill preterm neonates as well as to the survivors' longterm health and well-being. We anticipate that results from these exploratory studies will lead to important future studies examining additional mechanisms for, and consequences of, the effects of morphine on the developing cerebral circulation. PROJECT NARRATIVE: There is considerable debate regarding the risk-benefit ratio of our increasing clinical use of morphine in critically ill, non-surgical preterm infants. It is not known what the longterm effects of prolonged use of such a powerful drug may be on both cerebrovascular development and ultimately, function later in life. These proposed studies are designed to begin to fill some of the large knowledge gap in this important area.