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Mechanisms underlying TRPA1 receptor activation in inflammatory nociception and hyperalgesia


Recent studies have suggested that the TRPA1 ionotropic receptor plays an important role in conducing nociceptive information under peripheral inflammatory conditions. This receptor appears to be expressed exclusively in primary nociceptive neurons and it is activated in response to inflammatory mediators that activates phospholipase C signaling pathway. These characteristics make the TRPA1 receptor an interest potential target for the development of new drugs for pain control. This receptor is also directly gated by endogenous and exogenous chemicals through covalent modification. Recently it was demonstrated that formaldehyde is one of these chemicals and that the blockade of TRPA1 almost abolish formalin-induced nociception. Although it was suggested that the molecular mechanism of formalin-induced nociception is the direct activation of this receptor, it has been suggested that the mechanisms underlying a pain response associated with tissue damage and inflammation result from the co-activation on different receptors that activate independent and synergistic pathways. In accordance with this idea, it was demonstrated that formalin-induced nociception depends of the activation of H1 as well as 5-HT 1A e 3 receptors. The role of the TRPA1 receptor in the peripheral sensitization of nociceptors has received little attention, however, the activation or sensitization of TRPA1 by inflammatory mediators may contribute to lower the nociceptive threshold and consequently, to inflammatory hiperalgesia. Therefore, the first aim of his project is to test the hypothesis that the nociception induced in the formalin model depends on the co-activation of TRPA-1, H1 and 5-HT 1A e 3 receptors. With this purpose we will evaluate: (a) Whether the activation of each one of these receptors contributes in an independent but synergistic way to formalin-induced nociception. (b) Whether the activation of H1 and 5-HT 1A e 3 receptors activates the TRPA1 receptor. (c) Whether the formalin-induced activation of TRPA1 receptor contributes to the release of 5-hydroxytryptamine and histamine. The second aim of this project is to test the hypothesis that the TRPA1 receptor mediates the inflammatory mechanical hyperalgesia induced in the carrageenan model and if so whether indirect mechanisms mediated by an increase in leukocyte migration and inflammatory cytokinin expression. (AU)

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