The role of endocannabinoid system and TRPV1 receptors in the antidepressant and anxiolytic effects of dipyrone in chronic unpredictable mild stress in mice

Although dipyrone is a widely used analgesic and antipyretic, its mechanism of action is not fully clarified. Recent studies have drawn attention to its central effects and its relationship with the endocannabinoid system. The endocannabinoid system plays important roles in processes such as anxiety, depression, fear, and learning-memory. In this study, we aimed to investigate whether endocannabinoid levels change in the amygdala in chronic unpredictable mild stress model in mice and whether cannabinoid and TRPV1 receptors mediate antidepressant and anxiolytic effects of dipyrone. Mice were submitted to chronic unpredictable mild stress protocol of 6-weeks, then behavioral test were performed. In the first part of the study, dipyrone was injected at doses of 150, 300, and 600 mg/kg (i.p.) during behavioral tests. In the second part, the CB1 antagonist AM 251 (1 mg/kg, i.p.), the CB2 antagonist AM630 (1 mg/kg, i.p.), and the TRPV1 antagonist capsazepine (3 mg/kg, i.p.) were administered alone or in combination with 300 mg/kg dipyrone to observe if these receptors mediate dipyrone effects. Endocannabinoid and N-acylethanolamines levels were measured by LC-MS/MS in amygdala. Our results showed that there were no changes in AEA, 2-AG, PEA, OAE levels in the amygdala in mice exposed to chronic unpredictable mild stress model; dipyrone exerted antidepressant and anxiolytic effects at doses of 300 and 600 mg/kg; its anxiolytic effect appears to be mediated via CB1 receptors, whereas TRPV1 receptors seems to mediate its antidepressant action.