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 Discovery #1: Our recent unpublished findings indicate that high fat diet and alcohol induce increased expression of transient receptor potential vanilloid 4 (TRPV4) channels on pancreas cells.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.
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.
|Lyons, Danielle N; Zhang, Liping; Danaher, Robert J et al. (2017) PPAR? Agonists Attenuate Trigeminal Neuropathic Pain. Clin J Pain 33:1071-1080|
|McIlwrath, S L; Nesemeier, R; Ma, F et al. (2017) Inflammatory 'double hit' model of temporomandibular joint disorder with elevated CCL2, CXCL9, CXCL10, RANTES and behavioural hypersensitivity in TNFR1/R2-/- mice. Eur J Pain 21:1209-1223|
|Kaushal, R; Taylor, B K; Jamal, A B et al. (2016) GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NA?1 receptors in the medial prefrontal cortex. Neuroscience 334:148-159|
|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 ?-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|
|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|
|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|
|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|
|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|
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