In this grant, we propose an in vitro multidisciplinary study of the excitability changes in vagal afferent neurons produced by antigen challenge and by mast cell-derived degranulation products. Vagal afferents play an important role in reflex bronchoconstriction during anaphylactic reactions where their nerve endings in lung are excited by produced released from or generated by mast cell degranulation. Although neurogenic mechanisms have long been suspected to contribute to the pathology of allergic diseases, our knowledge of the communication between the principal immune cells which mediate immediate hypersensitivity (the mast cell) and sensory neurons is severely limited. We have found that extracts of purified and immunologically activated lung mast cells excite a subpopulation of visceral afferent neurons in the nodose ganglion of the rabbit by selectively blocking an unusually protracted spike afterhyperpolarization. Additionally, we have observed that mast cells in nodose ganglia isolated from actively sensitized guinea pigs release inflammatory mediators upon challenge with a specific antigen. Concomitantly, some nodose neurons showed persistent membrane depolarization. This proposal is part of our long-range goal of understanding the role of nerve-associated mast cells in health and disease. To this end, we will combine neurophysiological, immunological and morphological methodologies to increase our understanding of the communication that exists between mast cells and visceral afferent neurons. Specifically, studies utilizing intracellular current-and voltage-clamp and patch-clamp techniques will be carried out with nodose ganglion neurons of rabbit and guinea pig to: (1) define the membrane mechanisms responsible for antigen and mast cell-induced excitability changes; (2) characterize the nature of mediators responsible for these excitatory changes; and (3) examine the excitatory effects produced by extracts from purified and antigenically stimulated guinea pig lung mast cells. We will also delineate morphologic and histological features of mast cells in nodose ganglia and investigate how known inflammatory mediators alter vagal afferent excitability. These studies will add strong support for the hypothesis that IgE- mediated release of mast cell constituents directly affects sensory neurons.
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