Epoxy-eicosatrienoic acids (EETs) are molecules of intracellular lipid signaling that have important biological activities, such as vasodilation, anti-inflammation and analgesic effects. However, EETs have a very short half-life since they are rapidly hydrolyzed by the soluble epoxy hydrolase enzyme (sEH), reducing their bioavailability. Thus, the inhibitors of the sEH enzyme arouse great interest for therapeutic use. Recently, the research group of Dr. Bruce D. Hammock (UC - Davis, USA) developed and patented a sEH inhibitor, named 1-trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl) urea (TPPU), which presented potential analgesic and anti-inflammatory effects. However, the mechanisms of action related to these effects still need to be studied. Since EETs have a potent anti-inflammatory effect mediated by the activation of peroxisome proliferator-activated receptor gamma (PPAR-³), we hypothesized that TPPU enhances the expression of EETs, which is mediated by the activation of the PPAR-³ expressed in TMJ, exhibits a potent anti-inflammatory effect. In this study we will use the formalin-induced inflammatory hypernociception model in TMJ to evaluate: (1) the peripheral antinociceptive effect of TPPU on formalin-induced inflammatory hypernociception in TMJ of rats; (2) Evaluate whether the TPPU-induced antinociceptive effect on ATM is mediated by PPAR-³ receptor activation; (3) to investigate the effect of TPPU on the alteration of M1 and M2 macrophages phenotyping in TMJ. The development of this project will contribute to the elucidation of the mechanisms involved in the peripheral antinociceptive effect induced by TPPU in TMJ, allowing the development of more efficient pharmacological targets for the control of painful conditions of inflammatory origin.
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