TRPA1 receptor stimulation by hydrogen peroxide is critical to trigger pain during MSU-induced inflammation.

Objective: Gout is a common cause of inflammatory arthritis provoked by the accumulation of monosodium urate (MSU) crystals, but the underlying mechanisms of the pain in acute gout attacks are poorly understood. The aim of the present study was to evaluate the role of transient receptor potential ankyrin 1 (TRPA1) and TRPA1 stimulants, such as hydrogen peroxide (H2O2), in the MSU-induced inflammation model in rodents. Methods: MSU or H2O2 were injected into the hind paw of rodents, or applied in cultured sensory neurons and intracellular calcium in vitro and inflammatory or nociceptive responses in vivo were evaluated. Pharmacological, genetic or biochemical tools and methods have been used. Results: We found that TRPA1 antagonism, TRPA1 gene deletion or defunctionalization by capsaicin pretreatment of peptidergic TRP-expressing primary sensory neurons 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-detoxifing enzyme, catalase. H2O2, but not MSU, directly stimulated sensory neurons through the activation of TRPA1. Nociceptive responses evoked by MSU or H2O2 injection were attenuated by catalase, the reducing agent dithiothreitol. In addition, MSU injection increased the expression of TRPA1 and TRPV1 as well as enhanced cellular infiltration and IL-1β levels, which were blocked by TRPA1 antagonism. Conclusion: Our results suggest that MSU-injection increases tissue H2O2 thereby stimulating TRPA1 on sensory nerve endings to produce inflammation and nociception. TRPV1, by a hitherto unknown mechanism, also contributes to these responses.