Background: Recently, we demonstrated that the antipsychotic dopaminergic and serotoninergic agonist aripiprazole induced peripheral antinociception. However, the mechanism underlying this effect has not been fully established. Here, our aim was to identify possible relationships between this action of aripiprazole and the endocannabinoid system.
Methods: All drugs were given locally into the right hind paw of male Swiss mice weighing 30-35 g in a volume of 20 µL. The hyperalgesia was induced by intraplantar injection of prostaglandin E2 (2 μg). Aripiprazole was injected 10 minutes before the measurement, and an irreversible inhibitor of anandamide hydrolase (MAFP), an inhibitor for monoacylglycerol lipase (JZL184), and an anandamide reuptake inhibitor (VDM11) were given 10 minutes before the aripiprazole. Nociceptive thresholds were measured using an algesimetric apparatus in the third hour after prostaglandin E2 injection. Data were analyzed by ANOVA and Bonferroni tests.
Results: The antinociceptive effect induced by aripiprazole (100 μg) was blocked by cannabinoid 1 or 2 receptor antagonists AM251 (40 μg [P < .01], 80 μg [P < .0001], and 160 μg [P < .0001]) and AM630 (100 μg [P < .0001], 200 μg [P < .0001], and 400 μg [P < .0001]), respectively. The peripheral antinociception induced by aripiprazole (25 μg) was enhanced by administration of the inhibitor of fatty acid amide hydrolase (MAFP, 0.5 μg [P < .0001]) or monoacylglycerol lipase (JZL184, 4 μg [P < .0001]). Moreover, a similar enhancement was observed with the anandamide reuptake inhibitor (VDM11, 2.5 μg [P < .0001]).
Conclusions: These results provide evidence for the involvement of the endocannabinoid system in peripheral antinociception induced by aripiprazole treatment.