Alcohol and high fat induced chronic pancreatitis: TRPV4 antagonist reduces hypersensitivity.
Alcohol and high fat induced chronic pancreatitis: TRPV4 antagonist reduces hypersensitivity.
复制标题
酒精和高脂肪诱发的慢性胰腺炎：TRPV4 拮抗剂可降低超敏反应。
DOI：
10.1016/j.neuroscience.2015.10.028
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发表时间：
2015
期刊：
影响因子：
3.3
通讯作者：
Westlund,KN
中科院分区：
文献类型：
--
作者：
Zhang,LP;Kline4th,RH;Deevska,G;Ma,F;Nikolova-Karakashian,M;Westlund,KN
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, thein vivorole of transient receptor potential cation channel subfamily V member 4 (TRPV4) inchronicpancreatitis 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.
