Transient receptor potential ankyrin 1 mediates chronic pancreatitis pain in mice

Fiore Cattaruzza, Cali Johnson, Alan Leggit, Eileen Grady, A. Katrin Schenk, Ferda Cevikbas, Wendy Cedron, Sandhya Bondada, Rebekah Kirkwood, Brian Malone, Martin Steinhoff, Nigel Bunnett, Kimberly S. Kirkwood

Research output: Contribution to journalArticle

Abstract

Chronic pancreatitis (CP) is a devastating disease characterized by persistent and uncontrolled abdominal pain. Our lack of understanding is partially due to the lack of experimental models that mimic the human disease and also to the lack of validated behavioral measures of visceral pain. The ligand-gated cation channel transient receptor potential ankyrin 1 (TRPA1) mediates inflammation and pain in early experimental pancreatitis. It is unknown if TRPA1 causes fibrosis and sustained pancreatic pain. We induced CP by injecting the chemical agent trinitrobenzene sulfonic acid (TNBS), which causes severe acute pancreatitis, into the pancreatic duct of C57BL/6 trpa1+/+ and trpa1-/- mice. Chronic inflammatory changes and pain behaviors were assessed after 2-3 wk. TNBS injection caused marked pancreatic fibrosis with increased collagen-staining intensity, atrophy, fatty replacement, monocyte infiltration, and pancreatic stellate cell activation, and these changes were reflected by increased histological damage scores. TNBS-injected animals showed mechanical hypersensitivity during von Frey filament probing of the abdomen, decreased daily voluntary wheel-running activity, and increased immobility scores during open-field testing. Pancreatic TNBS also reduced the threshold to hindpaw withdrawal to von Frey filament probing, suggesting central sensitization. Inflammatory changes and pain indexes were significantly reduced in trpa1-/- mice. In conclusion, we have characterized in mice a model of CP that resembles the human condition, with marked histological changes and behavioral measures of pain. We have demonstrated, using novel and objective pain measurements, that TRPA1 mediates inflammation and visceral hypersensitivity in CP and could be a therapeutic target for the treatment of sustained inflammatory abdominal pain.

Original languageEnglish (US)
Pages (from-to)G1002-G1012
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume304
Issue number11
DOIs
StatePublished - 2013

Keywords

  • Chronic pancreatitis
  • Inflammation
  • Pain
  • Transient receptor potential ankyrin 1
  • Trinitrobenzene sulfonic acid

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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  • Cite this

    Cattaruzza, F., Johnson, C., Leggit, A., Grady, E., Katrin Schenk, A., Cevikbas, F., Cedron, W., Bondada, S., Kirkwood, R., Malone, B., Steinhoff, M., Bunnett, N., & Kirkwood, K. S. (2013). Transient receptor potential ankyrin 1 mediates chronic pancreatitis pain in mice. American Journal of Physiology - Gastrointestinal and Liver Physiology, 304(11), G1002-G1012. https://doi.org/10.1152/ajpgi.00005.2013