Neonatal Morphine: Long-term Cerebrovascular Effects

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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.