TRPA1 receptor stimulation by hydrogen peroxide is critical to trigger hyperalgesia and inflammation in a model of acute gout.
Acute gout attacks produce severe joint pain and inflammation associated with monosodium urate (MSU) crystals leading to oxidative stress production. The transient potential receptor ankyrin 1 (TRPA1) is expressed by a subpopulation of peptidergic nociceptors and, via its activation by endogenous reactive oxygen species, including hydrogen peroxide (H2O2), contributes to pain and neurogenic inflammation. The aim of this study was to investigate the role of TRPA1 in hyperalgesia and inflammation in a model of acute gout attack in rodents. Inflammatory parameters and mechanical hyperalgesia were measured in male Wistar rats and in wild-type (Trpa1(+/+)) or TRPA1-deficient (Trpa1(-/-)) male mice. Animals received intra-articular (ia, ankle) injection of MSU. The role of TRPA1 was assessed by receptor antagonism, gene deletion or expression, sensory fiber defunctionalization, and calcitonin gene-related peptide (CGRP) release. We found that nociceptor defunctionalization, TRPA1 antagonist treatment (via ia or oral administration), and Trpa1 gene ablation abated hyperalgesia and inflammatory responses (edema, H2O2 generation, interleukin-1β release, and neutrophil infiltration) induced by ia MSU injection. In addition, we showed that MSU evoked generation of H2O2 in synovial tissue, which stimulated TRPA1 producing CGRP release and plasma protein extravasation. The MSU-elicited responses were also reduced by the H2O2-detoxifying enzyme catalase and the reducing agent dithiothreitol. TRPA1 activation by MSU challenge-generated H2O2 mediates the entire inflammatory response in an acute gout attack rodent model, thus strengthening the role of the TRPA1 receptor and H2O2 production as potential targets for treatment of acute gout attacks.
Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil; Laboratory of Cellular and Molecular Biology, Graduate Program in Health Science, University of Southern Santa Catarina, Criciúma, SC, Brazil.
Gabriela
G
Trevisan
Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
Carin
C
Hoffmeister
Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil.
Mateus Fortes
MF
Rossato
Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil.
Sara Marchesan
SM
Oliveira
Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil.
Mariane Arnoldi
MA
Silva
Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil.
Cássia Regina
CR
Silva
Department of Health Sciences, University of Florence, Florence, Italy.
Camilla
C
Fusi
Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil.
Raquel
R
Tonello
Department of Health Sciences, University of Florence, Florence, Italy.
Daiana
D
Minocci
Department of Food Technology, Federal Technological University of Paraná, Medianeira Campus, Medianeira, PR, Brazil.
Gustavo Petri
GP
Guerra
Department of Health Sciences, University of Florence, Florence, Italy.
Serena
S
Materazzi
Department of Health Sciences, University of Florence, Florence, Italy.
Romina
R
Nassini
Department of Health Sciences, University of Florence, Florence, Italy.
Pierangelo
P
Geppetti
Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil; Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil; Department of Pharmacology, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil. Electronic address: ferreiraj99@gmail.com.
Juliano
J
Ferreira
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006073:Gout / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006930:Hyperalgesia / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D050052:TRPC Cation Channels / Q000378:metabolism*
D000975:Antioxidants; D050052:TRPC Cation Channels; D006861:Hydrogen Peroxide
CGRP; Free radicals; Gout; Hydrogen peroxide; IL-1β; Nociception