Our laboratory has made the initial observations suggesting that endogenous neuropeptide systems are related to neuro-oncogenicity and that perturbations of opiate receptor/endorphin interactions alter abnormal tissue growth. For example, continuous blockade of the opiate receptor by opioid antagonists (a) decreases the time prior to tumor appearance, (b) shortens survival time, and (c) increases tumor size in mice inoculated with neuroblastoma. The hypothesis of this proposal is that opiate receptors associated with neural tumor cells are related to growth processes, and that endorphins serve to regulate neoplasia through interaction with the opiate receptors. Murine neuroblastoma will be utilized to explore this thesis in both in vivo and in vitro experimentation. The present grant proposal is designed to elucidate the important of opiate receptors and endogenous opioids in regulating tumorigenesis and to ascertain the mechanisms responsible for these growth-related actions. The cellular mechanisms by which endogenous opioid systems might regulate response to transplanted neuroblastoma will be investigated by unbalancing endorphin/opiate receptor interactions during neuro-oncogenicity through continuous or intermittent receptor blockade with opioid antagonists. Cell prolifesration, differentiation, viabililty, and structure will be explored using histological, histochemical, and autoradiographic techniques. A special emphasis will be placed on defining the relationship between the cytoskeleton of tumor cells and endogenous opioid systems, and spectrin, tubulin, and actin will be immunocytochemically examined. Endorphin levels in tumor-bearing mice will be monitored by RIA in plasma and tumor tissue, and in association with endogenous opioid perturbation. Finally, the opiate receptor subtypes related to tumor growth will be determined. The number, affinity, and subtype of receptors in cultured cells will be assessed by opiate binding assays, and the effects of prototypic opioid ligands on cell growth, differentiation, and thy cytoskeleton defined. Opioid antagonist-induced supersensitivity will be evaluated by receptor assays and responsivity to prototypic opioid ligands. Additionally, tumor response to opioid antagonists selective for individual receptors will be tested. 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 growth of the nervous system.
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