We continue our previous focus on the biology and function of B-Endorphin (BE) in pituitary and brain. These systems will be studied under 2 types of conditions: 1) Steady state, involving the brain anatomy and region-specific processing. 2) After various challenges aimed at altering the demand on these systems, in order to understand their dynamics and regulatory principles. The anatomy of brain BE has been recently complicated by the discovery of a second cell group in the nucleus tractus solitarius (NTS). We shall describe the relative contribution of NTS versus arcuate cell groups to the BE brain pathways using lesion and tract tracing methods. Since post-translational modifications of BE can produce peptides with varying opioid activities (from highly potent to inactive), it is functionally relevant to continue to characterize region-specific processing, with particular attention to the cells of origin (i.e., arcuate vs NTS). Further, the processing of the other POMC domains will be examined in the context of the 2 brain systems. The challenge studies in the pituitary will assess changes in the cell biology at multiple levels of biosynthesis and release. We shall measure changes in peptide content, peptide forms in the gland and in blood, rates of biosynthesis processing of POMC and levels of POMC specific mRNA. The challenge studies in the anterior lobe will employ stressors and the secretagogue, corticotropin releasing factor. In the intermediate lobe, we shall use dopamine altering agents. The pituitary studies will allow us to elaborate on some insights we have gained into short term versus longer term regulatory strategies used by POMC cells. The challenge studies in brain are dependent on the convergence of the steady state studies on the one hand and the pituitary regulatory studies on the other. They are aimed at deriving brain indices of changes in BE activity in arcuate vs NTS systems. We shall rely on the measurement of multiple forms of BE and related peptides, and on quantitation of POMC mRNA in arcuate and NTS. The challenges will involve stress, brain stimulation and opiate addiction. This work should enable us to answer basic questions about brain BE, e.g., which is the actual product(s) in a given region. The indices derived should be valuable in understanding the functions of these potent endogenous opioids in modulating several behaviors including coping with pain and stress and opiate tolerance and dependence.
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