title: A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory hyperalgesia and Freund's complete adjuvant-induced monarthritis.
abstract: OBJECTIVE
  To investigate the involvement of transient receptor potential ankyrin 1 (TRPA1) in inflammatory hyperalgesia mediated by tumor necrosis factor α(TNFα) and joint inflammation.
  
  
  METHODS
  Mechanical hyperalgesia was assessed in CD1 mice, mice lacking functional TRP vanilloid 1 (TRPV1-/-) or TRPA1 (TRPA1-/-), or respective wildtype (WT) mice. An automated von Frey system was used, following unilateral intraplantar injection of TNFα or intraarticular injection of Freund's complete adjuvant (CFA). Knee swelling and histologic changes were determined in mice treated with intraarticular injections of CFA.
  
  
  RESULTS
  TNFα induced cyclooxygenase-independent bilateral mechanical hyperalgesia in CD1 mice. The selective TRPV1 receptor antagonist SB-366791 had no effect on mechanical hyperalgesia when it was coinjected with TNFα, but intrathecally administered SB- 366791 attenuated bilateral hyperalgesia, indicating the central but not peripheral involvement of TRPV1 receptors. A decrease in pain sensitivity was also observed in TRPV1-/- mice. Intraplantar coadministration of the TRPA1 receptor antagonist AP-18 with TNFα inhibited bilateral hyperalgesia. Intrathecal treatment with AP-18 also reduced TNFα-induced hyperalgesia. CFA-induced mechanical hyperalgesia in CD1 mice was attenuated by AP-18 (administered by intraarticular injection 22 hours after the administration of CFA). Furthermore, intraarticular CFA–induced ipsilateral mechanical hyperalgesia was maintained for 3 weeks in TRPA1 WT mice. In contrast, TRPA1-/- mice exhibited mechanical hyperalgesia for only 24 hours after receiving CFA.
  
  
  CONCLUSIONS
  Evidence suggests that endogenous activation of peripheral TRPA1 receptors plays a critical role in the development of TNFα-induced mechanical hyperalgesia and in sustaining the mechanical hyperalgesia observed after intraaarticular injection of CFA. These results suggest that blockade of TRPA1 receptors may be beneficial in reducing the chronic pain associated with arthritis.
authors.affiliation: King's College London British Heart Foundation Centre of Excellence, Waterloo Campus, London, UK.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Fernandes
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Russell
authors.forename: Domenico
authors.initials: D
authors.lastname: Spina
authors.forename: Jason J
authors.initials: JJ
authors.lastname: McDougall
authors.forename: Rabea
authors.initials: R
authors.lastname: Graepel
authors.forename: Clive
authors.initials: C
authors.lastname: Gentry
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Staniland
authors.forename: David M
authors.initials: DM
authors.lastname: Mountford
authors.forename: Julie E
authors.initials: JE
authors.lastname: Keeble
authors.forename: Marzia
authors.initials: M
authors.lastname: Malcangio
authors.forename: Stuart
authors.initials: S
authors.lastname: Bevan
authors.forename: Susan D
authors.initials: SD
authors.lastname: Brain
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D018771:Arthralgia / Q000139:chemically induced / Q000276:immunology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology*; D002934:Cinnamates / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005620:Freund's Adjuvant / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000276:immunology*; D007270:Injections, Intra-Articular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; 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*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D000813:Anilides; D002934:Cinnamates; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D005620:Freund's Adjuvant