Our laboratory has made the initial observations suggesting that endogenous opioid peptides are related to nervous system development, and that perturbations of endogenous opioid/opioid receptor interactions markedly influence the course of neuroontogeny (Science 221:1179-1180, 1983). During the first 2 years of this project, the role of endogenous opioid systems in brain development has been carefully defined. We found that endogenous opioids modulate neurobiological maturation, and influence both cell proliferation, and differentiation. A major discovery was that endogenous opioid systems are involved in human brain development. Our hypothesis is that endogenous opioids serve to control brain development through interaction with opioid receptors associated with developing neural cells; this may reflect an autocrine mechanism of growth. In this grant proposal, we continue to explore this thesis using the developing rat cerebella, as a model.
The aims of this proposal are: (1) Identify the prototypic opioids related to growth through drug displacement studies and structure-function experiments. The binding site related to growth will be fully characterized, including assessment of kinetics, saturation, and interactions. (2) determine the location and distribution of growth-related opioids by immunoelectron microscopy. (3) Investigate whether developing neural tissues synthesize opioid precursors using in situ hybridization. (4) Isolate and identify the opioid receptor related to neural growth, and characterize the receptor in terms of size, subunit composition, peptide maps, and binding function as studied by reconstitution experiments. Our research efforts will contribute to comprehending normal brain development, and will have impact on understanding the etiology or neurodevelopmental-based dysfunction. Information derived from these studies may be used in designing strategies for intervention in some developmental disorders of the nervous system. This research is part of a long- range program in cellular and molecular neurobiology which seeks to understand the fundamental principles underlying normal and abnormal brain development.
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