title: Transient receptor potential ankyrin 1 receptor stimulation by hydrogen peroxide is critical to trigger pain during monosodium urate-induced inflammation in rodents.
abstract: OBJECTIVE
  Gout is a common cause of inflammatory arthritis and is provoked by the accumulation of monosodium urate (MSU) crystals. However, the underlying mechanisms of the pain associated with acute attacks of gout are poorly understood. The aim of this study was to evaluate the role of transient receptor potential ankyrin 1 (TRPA-1) and TRPA-1 stimulants, such as H2 O2 , in a rodent model of MSU-induced inflammation.
  
  
  METHODS
  MSU or H2 O2 was injected into the hind paws of rodents or applied in cultured sensory neurons, and the intracellular calcium response was measured in vitro. Inflammatory or nociceptive responses in vivo were evaluated using pharmacologic, genetic, or biochemical tools and methods.
  
  
  RESULTS
  TRPA-1 antagonism, TRPA-1 gene deletion, or pretreatment of peptidergic TRP-expressing primary sensory neurons with capsaicin markedly decreased MSU-induced nociception and edema. In addition to these neurogenic effects, MSU increased H2 O2 levels in the injected tissue, an effect that was abolished by the H2 O2 -detoxifying enzyme catalase. H2 O2 , but not MSU, directly stimulated sensory neurons through the activation of TRPA-1. The nociceptive responses evoked by MSU or H2 O2 injection were attenuated by the reducing agent dithiothreitol. In addition, MSU injection increased the expression of TRPA-1 and TRP vanilloid channel 1 (TRPV-1) and also enhanced cellular infiltration and interleukin-1β levels, and these effects were blocked by TRPA-1 antagonism.
  
  
  CONCLUSIONS
  Our results suggest that MSU injection increases tissue H2 O2 , thereby stimulating TRPA-1 on sensory nerve endings to produce inflammation and nociception. TRPV-1, by a previously unknown mechanism, also contributes to these responses.
authors.affiliation: Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Trevisan
authors.forename: Carin
authors.initials: C
authors.lastname: Hoffmeister
authors.forename: Mateus F
authors.initials: MF
authors.lastname: Rossato
authors.forename: Sara M
authors.initials: SM
authors.lastname: Oliveira
authors.forename: Mariane A
authors.initials: MA
authors.lastname: Silva
authors.forename: Rafael P
authors.initials: RP
authors.lastname: Ineu
authors.forename: Gustavo P
authors.initials: GP
authors.lastname: Guerra
authors.forename: Serena
authors.initials: S
authors.lastname: Materazzi
authors.forename: Camilla
authors.initials: C
authors.lastname: Fusi
authors.forename: Romina
authors.initials: R
authors.lastname: Nassini
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D059787:Acute Pain / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D015210:Arthritis, Gouty / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014527:Uric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D016877:Oxidants; D011687:Purines; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D014527:Uric Acid; D006861:Hydrogen Peroxide