Sildenafil enhances the peripheral antinociceptive effect of ellagic acid in the rat formalin test

OBJECTIVE: Ellagic acid (EA), a major polyphenolic compound of pomegranate juice, produces antinociceptive effects, which are mediated through opioidergic and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathways. The present study was conducted to elucidate the peripheral antinociceptive effect of EA alone and in combination with sildenafil in the rat formalin test. MATERIALS AND METHODS: Pain was produced by intraplantar injection of formalin (2.5%) in rats and nociceptive behavior was measured as the number of flinches every 5 min in 60 min after injection. RESULTS: Local administration of EA and sildenafil dose-dependently increased the nociception threshold in both phases of the test. Moreover, sub-effective doses of sildenafil (25 or 50 mcg/paw, i.p.) significantly and dose-dependently enhanced the antinociception induced by a sub-effective dose of EA (60 mcg/paw, i.pl.) in both phases of the test. The antinociception produced by these drugs alone, or in combination, was due to a peripheral site of action, since the administration in the contralateral paw was ineffective. CONCLUSION: Our results suggest that EA has local peripheral antinociceptive activity, and enhancement of this effect with sildenafil probably occurs through the inhibition of cGMP metabolism.