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 H₂O₂, in a rodent model of MSU‐induced inflammation.Methods: MSU 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.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 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‐1β levels, and these effects were blocked by TRPA‐1 antagonism.Conclusion: Our 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.

The necessary dose of MSU to elicit 50% of the response relative to the control value] = 0.04 [95% confidence interval 0.01–0.11] mg/paw) and edema (ED50 = 0.08 [95% confidence interval 0.04–0.16] mg/paw) when injected into the hind paw of rats. Treatment with the selective TRPV1 receptor (also known as capsaicin receptor and vanilloid receptor-1) antagonists SB366791 or AMG9810 largely prevented nociceptive and edematogenic responses to MSU. Moreover, the desensitization of capsaicin-sensitive afferent fibers as well as pretreatment with the tachykinin NK1 receptor antagonist RP 67580 also significantly prevented MSU-induced nociception and edema. Once MSU was found to induce mast cell stimulation, we investigated the participation of these cells on MSU effects. Prior degranulation of mast cells by repeated treatment with the compound 48/80 decreased MSU-induced nociception and edema or histamine and serotonin levels in the injected tissue. Moreover, pretreatment with the mast cell membrane stabilizer cromolyn effectively prevented nociceptive and edematogenic responses to MSU. MSU induced a release of histamine, serotonin, and tryptase in the injected tissue, confirming mast cell degranulation. Furthermore, the antagonism of histaminergic H1 and serotoninergic receptors decreased the edema, but not the nociception of MSU. Finally, the prevention of the tryptase activity was capable of largely reducing both MSU-induced nociception and edema. Collectively, the present findings demonstrate that MSU produces nociceptive and edematogenic responses mediated by TRPV1 receptor activation and mast cell degranulation. Monosodium urate crystals produce nociceptive and edematogenic response mediated by TRPV1 receptor activation and mast cell degranulation....

The aim of the present study was to investigate the participation of TRPV1 in an acute gout attack model. Experiments were conducted to evaluate the participation of TRPV1 in the nociceptive and inflammatory responses (oedema, plasma extravasation, leucocyte infiltration and also IL-1β production) triggered by IA (ankle) administration of monosodium urate (MSU) in rats using selective antagonist TRPV1 receptor, defunctionalization of sensory fibres and increased immunoreactivity. We have also analysed the inflammatory response. The participation of mast cells in the MSU-induced nociception and inflammation was evaluated using a mast cell stabilizer and a mast cell degranulator compound. We observed that MSU (1.25 mg/site) injected into the rat ankle joint elicited ongoing pain-like behaviour, hyperalgesia, allodynia and articular oedema as well as plasma extravasation, leucocyte infiltration and IL-1β production in lavage fluid. All of these events were inhibited by the co-administration of the selective TRPV1 receptor antagonist SB366791 (10 nmol/site). MSU crystals also increased the immunoreactivity of the TRPV1 receptor in the articular tissue of injected animals. Furthermore, the defunctionalization of TRPV1-positive sensory neurons also significantly reduced MSU-induced ongoing pain-like behaviour, hyperalgesia and oedema. Thus we demonstrate that TRPV1 acts on sensory neurons and plays a relevant role in the nociception and inflammation induced by IA MSU, indicating it as a potential target to treat acute gout attacks.