For patients with inflamed or cancerous pancreas, the precipitating complaint is pain generated by local tissue inflammation, fibrosis, ductal stenosis, edema, and fluid pressure. The pain relayed by visceral afferent nerves from chronically inflamed pancreas can become severe and intractable with no effective long-term treatment options. The studies proposed in this competitive renewal extend the original aims of the parent grant with two serendipitously discovered novel and potentially related findings. Discovery #1: Our recent unpublished findings indicate that high fat diet and alcohol induce increased expression of transient receptor potential vanilloid 4 (TRPV4) channels on pancreas cells. TRPV4 channels are non-selective cation channels responsive to conditions present in the local cellular microenvironment after tissue injury, including lipid mediators and tissue edema. Some alcohol metabolites are lipid mediators that can activate TRPV4. Excessive TRPV4 activation initiates cellular influx of calcium that initiates damaging intracellular cascades and pancreas afferent nerve activation. Discovery #2: We found that pancreatic tissue damage, inflammation, and pain-related behaviors are significantly reduced by gene therapy inducing overexpression of the endogenous opioid peptide, met- enkephalin. We propose new studies using a chronic pancreatitis model in rats and clonal pancreatic cells to further investigate significant tissue injury-induced changes in the cell microenvironment that are relevant to inducible TRPV4 expression and activation responses during the development of chronic pain. Hypothesis: Alcohol-induced injury in pancreas cells increases TRPV4 expression and activation which are reduced by met-enkephalin protection Aim 1 Determine the effects of alcohol injury on TRPV4 expression and activation in the pancreas.
Aim 2 Determine if alcohol-induced TRPV4 expression and activation is reduced by met-enkephalin. Our overall goal is to discover local cellular microenvironment interactions that impact chronic pain and that provide inroads for development of future clinical treatments for chronic inflammatory visceral pain. The impact of TRPV4 induced in local reactive cells after tissue damage and the role of TRPV4 in chronic pain have not been well studied. The findings will provide knowledge about analgesic, protective and reparative effects of met-enkephalin related to TRPV4. Expected outcomes of challenging pancreatic cells in vitro with TRPV4 activators are that TRPV4 expression and activation responses will increase, except in the presence of met- enkephalin. Further, TRPV4 inhibitors and met-enkephalin will reduce pain-related behaviors in the rat model of chronic pancreatitis. The findings will extend understanding of TRPV4 mediated events in the local microenvironment that impact both peripheral and central sensitization during the transition from acute to chronic visceral pain. Study of the transition to chronic pain is a mission of the NIH Blueprint and NINDS.

Public Health Relevance

We propose that alcohol and other related injurious agents present in the inflamed pancreas increase expression and activation of the cation channel protein, transient receptor protein vanilloid 4 (TRPV4). We propose studies to confirm this preliminary finding and to determine if the endogenous opioid peptide met-enkephalin can interfere with the destructive actions induced by alcohol injury on TRPV4 expression and activation. Our novel findings have implications for improved pancreatic function and reduction of pain for patients with pancreatitis and pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039041-13
Application #
8494096
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Chen, Daofen
Project Start
2000-04-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
13
Fiscal Year
2013
Total Cost
$415,513
Indirect Cost
$135,706
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Lyons, D N; Kniffin, T C; Zhang, L P et al. (2015) Trigeminal Inflammatory Compression (TIC) injury induces chronic facial pain and susceptibility to anxiety-related behaviors. Neuroscience 295:126-38
Kline 4th, R H; Exposto, F G; O'Buckley, S C et al. (2015) Catechol-O-methyltransferase inhibition alters pain and anxiety-related volitional behaviors through activation of β-adrenergic receptors in the rat. Neuroscience 290:561-9
Zhang, L P; Kline 4th, R H; Deevska, G et al. (2015) Alcohol and high fat induced chronic pancreatitis: TRPV4 antagonist reduces hypersensitivity. Neuroscience 311:166-79
McIlwrath, Sabrina L; Westlund, Karin N (2015) Pharmacological attenuation of chronic alcoholic pancreatitis induced hypersensitivity in rats. World J Gastroenterol 21:836-53
Clark, S P; Bollag, W B; Westlund, K N et al. (2014) Pine oil effects on chemical and thermal injury in mice and cultured mouse dorsal root ganglion neurons. Phytother Res 28:252-60
Westlund, K N; Zhang, L P; Ma, F et al. (2014) A rat knockout model implicates TRPC4 in visceral pain sensation. Neuroscience 262:165-75
Zhang, Liping; Kline 4th, Robert H; McNearney, Terry A et al. (2014) Cannabinoid receptor 2 agonist attenuates pain related behavior in rats with chronic alcohol/high fat diet induced pancreatitis. Mol Pain 10:66
Zhang, L P; Ma, F; Abshire, S M et al. (2013) Prolonged high fat/alcohol exposure increases TRPV4 and its functional responses in pancreatic stellate cells. Am J Physiol Regul Integr Comp Physiol 304:R702-11
Westlund, Karin N; Zhang, Liping; Ma, Fei et al. (2012) Chronic inflammation and pain in a tumor necrosis factor receptor (TNFR) (p55/p75-/-) dual deficient murine model. Transl Res 160:84-94
Oz, Helieh S; Lu, Ying; Vera-Portocarrero, Louis P et al. (2012) Gene expression profiling and endothelin in acute experimental pancreatitis. World J Gastroenterol 18:4257-69

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