REGULATION OF VAGAL SUBSTANCE P SYNTHESIS IN VITRO

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Substance P, a widely distributed neuropeptide, has been identified within cell bodies of the sensory ganglia of the vagus nerve and the fibers emanating bidirectionally from them. Upon vagal sensory stimulation, substance P may be released not only at central terminals within the medulla oblongata but also at peripheral nerve endings where it may importantly influence cardiovascular, respiratory and gastrointestinal function. This project will study the factors, largely unknown, regulating the synthesis and transport of substance P within the sensory vagus nerve. Using explants of nodose ganglion and vagus nerve that have been demonstrated to synthesize and transport substance P in vitro for periods exceeding 24 hours, these studies will test the hypothesis that substance P synthesis is regulated in one of three ways: 1) by hormones or neurotransmitters acting directly on sensory cell bodies, 2) by the frequency or intensity of afferent neural stimulation or 3) by alterations in neurotransmission of the afferent (central) projection of the bipolar sensory fibers. Synthesis and transport of substance P and of de novo synthesized radiolabeled substance P will be measured during the addition to the explant medium of hormones or selected neurotransmitters or following electrical stimulation of explant peripheral and central projections. Changes in synthesis/transport will be correlated with alterations in two major intracellular second messenger systems, cyclic AMP and polyphosphoinositide metabolism. In vivo studies will also be performed to determine whether altered substance P synthesis and transport is coupled to similar changes in its basal and stimulated release at central brainstem and peripheral vagal sensory terminals. The vagus nerve has important functions in cardiovascular diseases such as arrythmia and hypertension, bronchospastic disorders of the lung and a variety of gastrointestinal disorders. Sensory vagus-contained substance P may play important afferent and efferent roles in those conditions. Understanding the regulation of its synthesis and transport will provide a groundwork for the recognition of and more selective therapeutic intervention in the vagal component of those disorders. These studies also will enhance understanding of substance P and neuropeptide regulation in other parts of the nervous system, including the brain.