? The goal of this revised application is to obtain support for the applicant such that he can focus his full time efforts on his research career and be released from his heavy teaching load. There are three major scientific aims of the research described in this application. The first major aim focuses on the basic biological mechanisms that underlie opiate tolerance and withdrawal in the infant and how those mechanisms differ with age. Although opiates continue to be the most important clinical tool available to treat pain in the infant patient, opiates also produce significant adverse effects including dependence and tolerance. The mechanisms of tolerance and dependence are different in the infant and the adult, making putative treatments for the adult inappropriate for the infant.
The second aim defines the developmental changes in the opioid and non-opioid mechanisms of nociception and antinociception. One of the limitations in the treatment of the seriously ill infant patient has been the limited understanding of how pain processing differs in the infant from the adult. Here we seek to understand the basic biological mechanisms that mediate nociception and antinociception in the infant and define how those mechanisms change over the course of development. Third, we characterize changes of sensory function and gene expression in the spinal cord after injury and after transplants of either fetal tissue or genetically modified cells that rescue function after that injury. Increased pain sensitivity, either as allodynia or hyperalgesia, is a serious and common consequence of spinal cord injury. Promising repair strategies that include transplants that secrete various growth factors may encourage increased peripheral input and enhanced pain even with improved motor function. Therefore we propose to assess changes in sensitivity to sensory stimuli following injury and treatment to determine whether or not treatments that promote repair and motor recovery also modify sensitivity to peripheral stimulation. In the studies described in this application, we propose a multidimensional approach, including behavioral, pharmacologic, anatomic and genetic methods. Many of these approaches were introduced into the applicant' s lab during the prior K02 support. Continuation of the K02 award, by reducing the PI's substantial teaching and administrative commitments, will allow him the resources to continue these studies, further his mentoring efforts, maintain his increased productivity, and continue his efforts to become involved in science policy and advocacy at the national and international levels. ? ? ? ?
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