Human infants are often exposed to opiate drugs because of illicit opiate use by the mother, or because of therapeutic use of methadone. The consequences of this exposure are largely unknown. Furthermore, pain is a significant clinical problem for preterm infants or full term infants undergoing medical procedures, in part because it can result in an established pain syndrome. Thus adequate and continued alleviation of pain is an important factor in the survival of human infants after major medical interventions. Yet adequate and safe relief of pain in neonates is a difficult clinical problem because these drugs act differently in the infant, with a different set of side effect. Little is known of the mechanisms of action of opiate drugs in the immature organism, following either illegal or therapeutic use. This application is for an independent research scientist award to allow the principal investigator to expand his work on the mechanisms of action of opiate drugs, and the biological processes that opiates affect. Several lines of research, partly funded by NIDA and NINDS, examine these problems. First, we define the development of inflammation and alterations in pain perception associated with inflammation during early development in the rat. We examine the effects of opiates on the pain process when given locally to the site of inflammation or centrally, and describe alterations in opiate receptors and peptides in neural and immune tissue as a result of inflammation. Second we propose to study the defensive response of the young animal to a variety of threatening stimuli, including pain, and study the role of central opioid systems in those responses. Third, we describe the role of various brain sites mediating the behavioral and affective consequences of opiate withdrawal and examine the behavioral effects, including changes mother-infant interactions, of spontaneous opiate withdrawal in the neonate. Finally, we will integrate these three lines of work by studying whether or not pain perception, defensive and autonomic responses to pain and other threats are altered in the infant undergoing opiate withdrawal. These experiment will provide data on the role of acute and chronic opiates in normal functioning and the response to significant environmental threats in the immature animal.
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