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. Recently, investigators have identified opiate receptors in developing brain and body tissues, endorphin immunoreactivity in the developing nervous system, and endorphins in the plasma and brain tissue of neonates. Questions as to the functional significance of endogenous opioid systems in early life have been raised. Our laboratory has now provided the first evidence that opiate receptors and endorphins are related to the regulation of normal body and brain development, and that their interaction in growth processes is extremely sensitive to perturbation. For example, continuous blockade of the opiate receptor by naltrexone, a potent and """"""""pure"""""""" opiate antagonist, during preweaning stages of rat neuro-ontogeny results in dramatic increases in brain size and cellular content. The present grant proposal is designed to elucidate the importance of opiate receptors and endogenous opioids in regulating neurobiological development and to ascertain the mechanisms responsible for these growth-related actions. Our strategy is to investigate the impact of continuous and intermittent opiate receptor blockade on neurogenesis and gliogenesis. Particular attention will be paid to the somatosensory cortex, hippocampus, and cerebellum during both the preweaning and postweaning periods, and histological, histochemical, morphometric, and biochemical techniques will serve in our assessment. The cellular mechanisms by which endogenous opioid systems regulate brain development will also be investigated. Cell proliferation, migration, and differentiation, as well as cell death, will be explored with light and electron microscopy and autoradiography. Since endorphins are suspected of participating in development, Beta-endorphin levels in plasma and brain tissue will be monitored. Finally, we will determine which opiate receptor subtypes are associated with mechanisms of growth. The number, affinity, subtypes, and anatomical location of opiate receptors during brain morphogenesis will be explored. Opiate receptor assays, in vitro autoradiography of receptor binding, and selective opiate antagonists will serve in our appraisal. 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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