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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology C Study Section (NEUC)
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University of Maryland Baltimore
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Swartz, Jessica B; Weinreich, Daniel (2009) Influence of vagotomy on monosynaptic transmission at second-order nucleus tractus solitarius synapses. J Neurophysiol 102:2846-55
Gover, T D; Moreira, T H; Weinreich, D (2009) Role of calcium in regulating primary sensory neuronal excitability. Handb Exp Pharmacol :563-87
Daher, João Paulo L; Gover, Tony D; Moreira, Thais H V et al. (2009) The identification of a caffeine-induced Ca2+ influx pathway in rat primary sensory neurons. Mol Cell Biochem 327:15-9
Bruno, Robert D; Gover, Tony D; Burger, Angelika M et al. (2008) 17alpha-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response. Mol Cancer Ther 7:2828-36
Laaris, N; Weinreich, D (2007) Prostaglandin E2 depresses solitary tract-mediated synaptic transmission in the nucleus tractus solitarius. Neuroscience 146:792-801
Veiga Moreira, T H; Gover, T D; Weinreich, D (2007) Electrophysiological properties and chemosensitivity of acutely dissociated trigeminal somata innervating the cornea. Neuroscience 148:766-74
Gover, Tony D; Moreira, Thais H V; Kao, Joseph P Y et al. (2007) Calcium homeostasis in trigeminal ganglion cell bodies. Cell Calcium 41:389-96
Gover, Tony D; Moreira, Thais H V; Kao, Joseph P Y et al. (2007) Calcium regulation in individual peripheral sensory nerve terminals of the rat. J Physiol 578:481-90
Oh, Eun Joo; Mazzone, Stuart B; Canning, Brendan J et al. (2006) Reflex regulation of airway sympathetic nerves in guinea-pigs. J Physiol 573:549-64
Hoesch, Robert E; Weinreich, Daniel; Kao, Joseph P Y (2004) Localized IP3-evoked Ca2+ release activates a K+ current in primary vagal sensory neurons. J Neurophysiol 91:2344-52

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