Alcohol and high fat induced chronic pancreatitis: TRPV4 antagonist reduces hypersensitivity. (17th December 2015)

• Record Type: Journal Article
• Authors: Zhang, L.P.; Kline, R.H.; Deevska, G.; Ma, F.; Nikolova-Karakashian, M.; Westlund, K.N.
• Is Part Of: Neuroscience. Volume 311(2015)
• Page Start: 166
• Page End: 179
• Publication Date: 2015-12-17
• Subjects: ABC avidin–biotin complex -- ABWL abdominal withdrawal latency -- AHF alcohol/high fat diet -- ANOVA analysis of variance -- CNS central nervous system -- ENK Enkephalin -- IBD inflammatory bowel diseases -- MDA malondialdehyde -- MnSOD manganese superoxide dismutase -- MOR μ-opioid receptors -- PWT paw withdrawal threshold -- TBA thiobarbituric acid -- TBARS thiobarbituric acid reactive substances -- TRPV4 transient receptor potential cation channel subfamily V member 4; TBARS -- rat -- HC 067047 -- visceral pain -- behavior -- loperamide; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2015.10.028
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Pain like behaviors develop in an alcohol high fat-fed rat pancreatitis model. Pain associated with AHF pancreatitis was alleviated by a TRPV4 channel antagonist. Pain associated with AHF pancreatitis was alleviated by the peripherally restricted μ-opiate receptor agonist, loperamide. Similarity of results for the TRPV4 channel antagonist to those with loperamide suggests TRPV4 is acting peripherally. TRPV4 channel is a potential therapeutic target for pancreatitis pain. Abstract: The pathogenesis of pain in chronic pancreatitis is poorly understood, and its treatment can be a major clinical challenge. Surgical and other invasive methods have variable outcomes that can be unsatisfactory. Therefore, there is a great need for further discovery of the pathogenesis of pancreatitis pain and new therapeutic targets. Human and animal studies indicate a critical role for oxidative stress and activation of transient receptor potential (TRP) cation channel subfamily members TRPV1 and TRPA1 on pancreatic nociceptors in sensitization mechanisms that result in pain. However, the in vivo role of transient receptor potential cation channel subfamily V member 4 (TRPV4) in chronic pancreatitis needs further evaluation. The present study characterized a rat alcohol/high fat diet (AHF)-induced chronic pancreatitis model with hypersensitivity, fibrotic pathology, and fat vacuolization consistent with the clinical syndrome. The rats with AHF-induced pancreatitis develop referred visceral pain-like behaviors, i.e. decreased hindpaw mechanical thresholds and shortened abdominal and hindpaw withdrawal latency to heat. In this study, oxidative stress was characterized as well as the role of TRPV4 in chronic visceral hypersensitivity. Lipid peroxidase and oxidative stress were indicated by increased plasma thiobarbituric acid reactive substances (TBARS) and diminished pancreatic manganese superoxide dismutase (MnSOD). The secondary sensitization associated with AHF-induced pancreatitis was effectively alleviated by the TRPV4 antagonist, HC 067047. Similarity of the results to those with the peripherally restricted μ-opiate receptor agonist, loperamide, suggested TRPV4 channel activated peripheral sensitization. This study using a reliable model that provides pre-clinical correlates of human chronic pancreatitis provides further evidence that TRPV4 channel is a potential therapeutic target for treatment of pancreatitis pain.