title: Synergistic role of TRPV1 and TRPA1 in pancreatic pain and inflammation.
abstract: OBJECTIVE
  The transient receptor potential (TRP) channels TRPV1 and TRPA1 have each been associated with regulation of efferent properties of primary afferent neurons that initiate neurogenic inflammation and are required for the development of inflammatory hyperalgesia. To evaluate the role of these channels in producing pain during pancreatic inflammation, we studied pancreatic nodose ganglion (NG) and dorsal root ganglion (DRG) sensory neurons (identified by content of retrograde tracer) and behavioral outcomes in a mouse model of acute pancreatitis.
  
  
  METHODS
  Pancreatic inflammation was induced by 8 hourly injections of cerulein (50 μg/kg). The extent of inflammation, pancreatic neuron TRP channel expression and function and excitability, and pain-related behaviors were evaluated over the course of the following week.
  
  
  RESULTS
  Histology and myeloperoxidase activity confirmed pancreatic inflammation that was associated with increased excitability and messenger RNA expression of the TRP channels in NG and DRG pancreatic neurons. Calcium imaging of pancreatic NG and DRG neurons from mice given cerulein revealed increased responses to TRP agonists. TRPV1 and TRPA1 antagonists attenuated cerulein-induced pain behaviors and pancreatic inflammation; they had a synergistic effect.
  
  
  CONCLUSIONS
  Pancreatic inflammation significantly increased the expression and functional properties of TRPV1 and TRPA1, as well as the excitability of pancreatic sensory neurons in vagal and spinal pathways. TRP channel antagonists acted synergistically to reverse pancreatic inflammation and associated pain behaviors; reagents that target interactions between these channels might be developed to reduce pain in patients with acute pancreatitis.
authors.affiliation: Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. schwartzee@upmc.edu
authors.forename: Erica S
authors.initials: ES
authors.lastname: Schwartz
authors.forename: Julie A
authors.initials: JA
authors.lastname: Christianson
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Chen
authors.forename: Jun-Ho
authors.initials: JH
authors.lastname: La
authors.forename: Brian M
authors.initials: BM
authors.lastname: Davis
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Albers
authors.forename: G F
authors.initials: GF
authors.lastname: Gebhart
mesh_terms: D015746:Abdominal Pain / Q000188:drug therapy / Q000209:etiology / Q000276:immunology; D000083:Acetanilides / Q000494:pharmacology*; D000178:Acrylamides / Q000494:pharmacology*; D000208:Acute Disease; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009620:Nodose Ganglion / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010179:Pancreas / Q000276:immunology / Q000294:innervation; D010195:Pancreatitis / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D018408:Patch-Clamp Techniques; D011687:Purines / Q000494:pharmacology*; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; C500530:3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide; D000083:Acetanilides; D000178:Acrylamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011687:Purines; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D002118:Calcium