Sensory nerves in the esophagus are essential for the regulation of its physiological function. Sensory nerves also mediate conscious sensations (heartburn, pain) and defensive reflexes from the esophagus. Perverted function of esophageal sensory nerves may result in pain and dysfunction disproportionate to the tissue injury. In many instances, the consequences of the esophageal sensory nerve activation present diagnostic and therapeutic dilemmas such as functional heartburn or non-cardiac chest pain (NCCP) originating in the esophagus. Despite their importance, the molecular mechanisms underlying esophageal sensations remain poorly understood. Progress in this area has been especially limited when it comes to the basic biology of the afferent pain fibers (nociceptors) in the esophagus. Accordingly, this proposal centers specifically on esophageal nociceptive nerves and the molecular mechanisms of their activation.
In Aim 1 we address our novel hypothesis that, based on embryonic origin, there are at least two distinct nociceptive nerve subtypes in the esophagus. These subtypes differ in both activation profile and neurotransmitter chemistry.
In Aim 2 and Aim 3 we address hypotheses relating to the mechanisms by which certain key mediators of esophageal sensations, acid and adenosine, evoke action potential discharge in the nerve terminals of esophageal nociceptors. Acid in the esophagus initiates disparate sensations including heartburn and pain. Adenosine has been recently implicated in non-cardiac chest pain.
In aim 2 we will combine molecular biological and electrophysiological techniques to evaluate our hypothesis that acid activates esophageal nociceptors via certain acid sensing ion channels (ASIC) in addition to the capsaicin-sensitive TRPV1 receptor.
In aim 3 we will investigate the nature of ion channels involved in adenosine receptor-mediated action potential discharge in esophageal nociceptive terminals. We hypothesize that the G-protein linked adenosine receptors mediate activation of esophageal nociceptors by a signal transduction scheme that results in opening certain chloride channels and TRPV1. We will address our hypotheses using a combination of anatomical and various electrophysiological techniques in wild type mice and mice with strategic genetic mutations.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
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Hamilton, Frank A
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Brozmanova, M; Mazurova, L; Ru, F et al. (2016) Mechanisms of the adenosine A2A receptor-induced sensitization of esophageal C fibers. Am J Physiol Gastrointest Liver Physiol 310:G215-23
Hennel, Michal; Brozmanova, Mariana; Kollarik, Marian (2015) Cough reflex sensitization from esophagus and nose. Pulm Pharmacol Ther 35:117-21
Ru, F; Banovcin Jr, P; Kollarik, M (2015) Acid sensitivity of the spinal dorsal root ganglia C-fiber nociceptors innervating the guinea pig esophagus. Neurogastroenterol Motil 27:865-74
Dusenkova, Svetlana; Ru, Fei; Surdenikova, Lenka et al. (2014) The expression profile of acid-sensing ion channel (ASIC) subunits ASIC1a, ASIC1b, ASIC2a, ASIC2b, and ASIC3 in the esophageal vagal afferent nerve subtypes. Am J Physiol Gastrointest Liver Physiol 307:G922-30
Halicka, J; Banovcin Jr, P; Halickova, M et al. (2014) Acid infusion into the esophagus increases the number of meal-induced transient lower esophageal sphincter relaxations (TLESRs) in healthy volunteers. Neurogastroenterol Motil 26:1469-76
Surdenikova, L; Ru, F; Nassenstein, C et al. (2012) The neural crest- and placodes-derived afferent innervation of the mouse esophagus. Neurogastroenterol Motil 24:e517-25
Brozmanova, Mariana; Mazurova, Lenka; Ru, Fei et al. (2012) Comparison of TRPA1-versus TRPV1-mediated cough in guinea pigs. Eur J Pharmacol 689:211-8
Ru, F; Surdenikova, L; Brozmanova, M et al. (2011) Adenosine-induced activation of esophageal nociceptors. Am J Physiol Gastrointest Liver Physiol 300:G485-93
Brozmanova, M; Ru, F; Surdenikova, L et al. (2011) Preferential activation of the vagal nodose nociceptive subtype by TRPA1 agonists in the guinea pig esophagus. Neurogastroenterol Motil 23:e437-45
Kollarik, M; Carr, M J; Ru, F et al. (2010) Transgene expression and effective gene silencing in vagal afferent neurons in vivo using recombinant adeno-associated virus vectors. J Physiol 588:4303-15

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