title: Transient receptor potential ankyrin 1 mediates chronic pancreatitis pain in mice.
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.
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Fiore
authors.initials: F
authors.lastname: Cattaruzza
authors.forename: Cali
authors.initials: C
authors.lastname: Johnson
authors.forename: Alan
authors.initials: A
authors.lastname: Leggit
authors.forename: Eileen
authors.initials: E
authors.lastname: Grady
authors.forename: A Katrin
authors.initials: AK
authors.lastname: Schenk
authors.forename: Ferda
authors.initials: F
authors.lastname: Cevikbas
authors.forename: Wendy
authors.initials: W
authors.lastname: Cedron
authors.forename: Sandhya
authors.initials: S
authors.lastname: Bondada
authors.forename: Rebekah
authors.initials: R
authors.lastname: Kirkwood
authors.forename: Brian
authors.initials: B
authors.lastname: Malone
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
authors.forename: Nigel
authors.initials: N
authors.lastname: Bunnett
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Kirkwood
mesh_terms: D000818:Animals; D059333:Central Nervous System Sensitization / Q000235:genetics; D004195:Disease Models, Animal; D005355:Fibrosis / Q000235:genetics; D007249:Inflammation / Q000235:genetics; D015601:Injury Severity Score; D008124:Locomotion / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000235:genetics*; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology; D059265:Visceral Pain / Q000235:genetics
chemical_list: D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D014302:Trinitrobenzenesulfonic Acid
keywords: chronic pancreatitis; inflammation; pain; transient receptor potential ankyrin 1; trinitrobenzene sulfonic acid
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