Stimulation of primary sensory neurons produces local vasodilation, plasma extravasation, and pain and is due largely to release of the neuropeptides substance P and calcitonin gene-related peptide (CGRP). Pathological activation of sensory neurons and the inflammatory sequelae are known as neurogenic inflammation and appear to be important in many organs systems including the pancreas. Factors that stimulate primary sensory neurons include hydrogen ions, heat, leukotrienes, arachidonic acid metabolites, bradykinin, and proteases such as trypsin, all of which may participate in the generation of acute pancreatitis. The current proposal examines the cellular and molecular mechanisms involved in sensory nerve activation within the pancreas and the contribution of neurogenic inflammation to the pathogenesis of pancreatitis. Primary sensory neurons are capsaicin-sensitive and express the capsaicin receptor [known as transient receptor potential vanilloid 1 (TRPV1)]. The PI has demonstrated that TRPV1 is activated in several models of pancreatitis including caerulein-induced pancreatitis and has extensive pharmacological data indicating that TRPV1 inhibition reduces the severity of pancreatitis. TRPV1 is activated by heat and protons, but it is unlikely that either high body temperature or acid directly activate TRPV1 in vivo. We have demonstrated that close arterial injection of leukotriene B4 (LTB4) into the pancreas causes pancreatic inflammation similar to caerulein and that this effect is blocked by an TRPV1 antagonist. Importantly, ethanol has been shown to lower the activation threshold of TRPV1 and we propose that ethanol may contribute to pancreatitis by activating primary sensory neurons. The current application is designed to test the hypothesis that primary sensory innervation is a necessary component of pancreatitis. The goal of this project is to define the events resulting from pancreatic injury that lead to sensory nerve activation and the initiation of pancreatitis. Studies will utilize recently developed rodent models to examine the following Specific Aims: (1) Characterize the mechanism by which LTB4 activates primary sensory nerves and induces pancreatitis; (2) Determine the role of TRPV1 in experimental ethanol-induced pancreatitis;and (3) Determine the relationship between tumor necrosis factor ? (TNF?) and TRPV1 in experimental pancreatitis. These results should help both elucidate the importance of primary sensory innervation in the pathogenesis of pancreatitis and provide possible new strategies for the treatment of pancreatitis.

Public Health Relevance

Pancreatitis is an inflammatory disease of the pancreas that causes intense pain and, in severe cases, death. Although some predisposing factors (such as gallstones and alcohol) are known, the exact mechanisms leading to pancreatitis are not well understood. Pain-sensing nerves release transmitters that may actually cause inflammation and preliminary data indicate that these nerves play a role in pancreatitis. This proposal will characterize the neural mechanisms that contribute to pancreatitis and may lead to improved treatments of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064213-10
Application #
8477177
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Serrano, Jose
Project Start
2003-04-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2013
Total Cost
$320,909
Indirect Cost
$115,198
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Kanju, Patrick; Chen, Yong; Lee, Whasil et al. (2016) Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain. Sci Rep 6:26894
Bohórquez, Diego; Haque, Fariha; Medicetty, Satish et al. (2015) Correlative Confocal and 3D Electron Microscopy of a Specific Sensory Cell. J Vis Exp :e52918
Shahid, Rafiq A; Vigna, Steven R; Layne, Amanda C et al. (2015) Acinar Cell Production of Leukotriene B4 Contributes to Development of Neurogenic Pancreatitis in Mice. Cell Mol Gastroenterol Hepatol 1:75-86
Shahid, Rafiq A; Wang, David Q-H; Fee, Brian E et al. (2015) Endogenous elevation of plasma cholecystokinin does not prevent gallstones. Eur J Clin Invest 45:237-46
Chandra, Rashmi; Liddle, Rodger A (2014) Recent advances in the regulation of pancreatic secretion. Curr Opin Gastroenterol 30:490-4
Vigna, Steven R; Shahid, Rafiq A; Liddle, Rodger A (2014) Ethanol contributes to neurogenic pancreatitis by activation of TRPV1. FASEB J 28:891-6
Chandra, Rashmi; Liddle, Rodger A (2013) Modulation of pancreatic exocrine and endocrine secretion. Curr Opin Gastroenterol 29:517-22
Chandra, Rashmi; Wang, Yu; Shahid, Rafiq A et al. (2013) Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion. J Clin Invest 123:3343-52
Forsmark, Chris E; Liddle, Rodger A (2012) The challenging task of treating painful chronic pancreatitis. Gastroenterology 143:533-5

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