Journal
ARTHRITIS AND RHEUMATISM
Volume 65, Issue 11, Pages 2984-2995Publisher
WILEY
DOI: 10.1002/art.38112
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Funding
- Conselho Nacional de Desenvolvimento Cientifico
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- Programa de Apoio aos Nucleos de Excelencia
- Fundacao de Ampara a Pesquisa do Estado do Rio Grande Sul, Brazil
- PRODOC/CAPES
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil
- Ente Cassa di Risparmio di Firenze, Italy
- Italian Institute of Technology
- Tuscany Region
- Italian Ministry of Education Universities and Research
- Ente Cassa di Risparmio di Firenze
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ObjectiveGout 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 H2O2, in a rodent model of MSU-induced inflammation. MethodsMSU or H2O2 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. ResultsTRPA-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 H2O2 levels in the injected tissue, an effect that was abolished by the H2O2-detoxifying enzyme catalase. H2O2, but not MSU, directly stimulated sensory neurons through the activation of TRPA-1. The nociceptive responses evoked by MSU or H2O2 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-1 levels, and these effects were blocked by TRPA-1 antagonism. ConclusionOur results suggest that MSU injection increases tissue H2O2, 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.
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