EC Paediatrics

Epoxyeicosatrienoic acids (EETs) are cytochrome P450-epoxygenase-derived metabolites of arachidonic acid that act as endogenous signaling molecules in multiple biological systems, including their controversial effects on nociception. The EETs and the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) originate from the same precursor, arachidonic acid, and share similar structural characteristics. Different isomers of EETs were described as capable of binding in cannabinoid receptors in rats' brains. To verify whether the peripheral antinociceptive effect of EETs depends on the mechanisms of the cannabinoid system. The mechanical paw pressure test was used to induce hyperalgesia by intraplantar injection of prostaglandin E2, evaluating the effect of exogenous EET administration and its interaction with the antagonism of CB₁/CB₂ receptors and the modulation of endocannabinoids. The EETs (5,6-, 8,9-, 11,12-, and 14,15-EET) and the drugs of the cannabinoid system were administered intraplantarly to male Swiss mice (n = 4). Statistical analysis was performed using ANOVA and the Bonferroni post hoc test. The selective CB₁ cannabinoid receptor antagonist, AM251, reversed the antinociceptive effect of EETs in a dose-dependent manner. Otherwise, the selective CB₂ cannabinoid receptor antagonist, AM630, did not reverse the antinociceptive effect of EETs. Furthermore, an endocannabinoid reuptake inhibitor (VDM11) and an enzyme inhibitor responsible for anandamide degradation (MAFP) potentiated the antinociceptive effect of low doses of EETs. On the other hand, an inhibitor of the enzyme responsible for the diacylglycerol lipase hydrolysis (JZL184) did not potentiate this effect. Our findings showed that the peripheral antinociceptive effect of 5,6-, 8,9-, 11,12-, and 14,15-EET could be due to the release of the endocannabinoid anandamide and subsequent activation of the CB₁ receptor, but not the CB₂ receptor, at the peripheral level, thereby inhibiting PGE₂-induced hyperalgesia.

 Keywords: Epoxyeicosatrienoic Acids; EETs; Cannabinoids; Anandamide; Antinociception

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