This project is based on the assumption that knowledge of the central homeostatic mechanisms that regulate airway functions is of critical importance in understanding the link between the nervous system and pathophysiology of airway disorders such as bronchial asthma and chronic obstructive bronchitis. In the proposed studies, which are a logical continuation of the ongoing work in this laboratory, we will identify brainstem 2nd order neurons within the nucleus tractus solitarius (nTS) which receive excitatory inputs from airway sensory sites, and study the neurotransmitter phenotype and receptor make-up of these neurons. In 0addition, we will define the role of excitatory amino acids and tachykinin 1peptides in transmission of signals from primary sensory cells onto second order (nTS) neurons, and their role in subsequent transmission of signals to airway related vagal preganglionic cells. Our studies will test the hypothesis that tonic cholinergic activity, reflexly induced airway constriction and submucosal gland secretion are mediated primarily via release of endogenous excitatory amino acids and co-release of substance p. In the proposed studies we will use 1) molecular biological approaches such as expression of c-Fos protein, encoded by the c-fos gene, to identify neurons in the nTS which are activated by stimulation of bronchopulmonary sensory receptors, 2) receptor immunocytochemistry and confocal microscopy to determine receptor(s) expressed by nTS sensory neurons and airway-related vagal preganglionic cells, 3) microdialysis and in situ voltametry, to measure neurotransmitter release, 4) selective receptor blockade and physiologic techniques to determine the role of receptors studied on reflex bronchoconstriction and reflex increase in submucosal gland secretion. The present proposal will provide information on the functional neurochemical anatomy of central regulation of cholinergic outflow, on neurotransmitter and receptor subtypes mediating airway responses to peripheral afferent inputs, and on interaction between neurochemicals that might set the stage for airway hypersensitivity and hyperreactivity.
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