Involvement of opioid receptors in the systemic and peripheral antinociceptive actions of ellagic acid in the rat formalin test

Ellagic acid (EA) produced antinociceptive and anti-inflammatory effects. This study was conducted to investigate the involvement of opioid receptors in the systemic and peripheral antinociceptive effects of EA after intraperitoneal (i.p.) and intraplantar (i.pl.) administration in the rat formalin assay. The results showed that i.p. administration of EA (1-30 mg/kg) dose-dependently attenuated flinching number in both early and late phases of the formalin test with mean ED50 values of 1.86 and 0.52 mg/kg, respectively. Moreover, this effect of EA at a dose of 30 mg/kg was comparable to that of morphine (5 mg/kg; i.p.) and indomethacin (10 mg/kg; i.p.). It was also demonstrated that administration of EA (30-300 μg/paw; i.pl.) resulted in dose-dependent peripheral antinociception against early and late phases of formalin-induced nociception with mean ED50 values of 47.64 and 71.78 μg/paw, respectively. The antinociception produced by the i.pl. injection was due to a local action, as its administration in the contralateral paw was ineffective. Furthermore, pre-treatment with naloxone, a non-selective opioid antagonist, significantly alleviated the systemic and peripheral antinociceptive effects of EA. Also, EA treatment had no effect on the motor activity of rats when tested in open-field task. Our data suggest that the systemic and peripheral antinociception activities of EA were mediated through the opioid receptors in the periphery and also in the central nervous system.