Alcohol and high fat induced chronic pancreatitis: TRPV4 antagonist reduces hypersensitivity

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 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.

Genetically inducedvs.classical animal models of chronic pancreatitis: a critical comparison

“…The rats developed a mild pancreatitis within 10-12 wk, presenting with acinar cell atrophy, fibrosis, vacuolization from fat deposition, and mild endocrine insufficiency from islet atrophy. Moreover, the rats showed visceral pain-like hypersensitivity evoked by mechanical and heat stimuli, suggesting altered nociception (15,47). In addition, histopathology and pain-related behavioral results correlated with each other (14).…”

Regulation of Pain and Itch by TRP Channels

“…Tumor necrosis factor-a increases responses to the TRPV4activator 4a-PDD in control PSCs [294]. Furthermore, inhibition of TRPV4 by systemic injection of the selective blocker HC067047 effectively alleviates the mechanical and thermal hypersensitivity of rats with HFA-induced chronic pancreatitis in a dose-dependent manner [295]. In the laboratory of the senior author, we recently found that blockade of both TRPV4 and TRPA1 by intraperitoneal injection of the dual inhibitor compound 16-8 dramatically attenuates the pancreatic edema and inflammation induced by caerulein.…”

Localisation analysis of nerves in the mouse pancreas reveals the sites of highest nerve density and nociceptive innervation

“…Therefore, future studies should increasingly apply 3D reconstruction and imaging technologies 8,9 for comparative analyses on human and mouse pancreas.Third,welimitedourstudytotheanalysisofneuropeptides likeVIP,SP,CGRP,andnNOSwithregardtosensationandpain,yet these analyses can certainly be expanded to include further neuronalsubgroups,includingTRPV1-,PACAP,5-HT,TRPA1-orTRPV4containing fiber subclasses. 48,49 Inconclusion,thepresentstudyprovidedadetailedquantitative illustration of the innervation and nociceptive fiber distribution in the mouse pancreas. Importantly, intrapancreatic nerves in mice appear asclustersofnumeroussmall-to-largenervetrunksaroundtwospecial niches, that is, the "perivascular" and "intrapancreatic perilymphoid"areas.Therefore,mouseintrapancreaticnervesexhibitmajor morphological differences when compared to human intrapancreatic nervesandareverydifficulttoanalyzewithineffortsofmurinemodellingofhumanpancreaticdisease(Table2).However,mousemodels will certainly continue to be of major benefit for understanding the molecular, genetic, and cellular repertoire of pancreatic diseases duringtheirdevelopmentandprogression.Still,aone-to-onetransfer ofconclusionsfromanatomic-histologicalobservationsinthemouse model to human disease should be avoided.…”