Involvement of L-arginine/NO/cGMP/KATP channel pathway in the peripheral antinociceptive actions of ellagic acid in the rat formalin test

• Intraplantar injection of ellagic acid produces antinociception in formalin test.
• Local l-NAME, methylene blue and glibenclamide reversed the EA antinociception.
• Local l-arginine and nitroprusside potentiated the EA-induced antinociception.
• NO–cGMP–KATP channel pathway is involved in the peripheral antinociception of EA.

The present study was conducted to evaluate the local antinociceptive actions of EA and the possible involvement of l-arginine/NO/cGMP/KATP channel pathway in this effect using formalin test in rats. To evaluate the involvement of l-arginine/NO/cGMP/KATP channel pathway in the antinociceptive action of EA, rats were pre-treated intraplantarlly with l-NAME (NOS inhibitor, 25-100 μg/paw), methylene blue (guanylyl cyclase inhibitor, 100-400 μg/paw), glibenclamide (ATP-sensitive K+ channel blocker, 25-100 μg/paw), l-arginine (a nitric oxide precursor, 25-100 μg/paw) and sodium nitroprusside (125-500 μg/paw). The local peripheral ipsilateral, but not contralateral, administration of EA into the right paw (30-300 μg/paw) produced a dose-related antinociception during both early and late phases of formalin test which is comparable with morphine (25 μg/paw). Moreover, local pre-treatment with l-NAME, methylene blue and glibenclamide dose-dependently prevented EA (100 μg/paw)-induced antinociception in late phase. Additionally, administration of l-arginine and sodium nitroprusside significantly potentiated the antinociception induced by EA in the late phase. However, these treatments had no significant effect on antinociceptive response of EA in the early phase of the formalin test. The results of the present study showed that EA-induced local peripheral antinociception during the both phases of formalin test. Also, our data suggested the activation of the l-arginine/NO/cGMP/KATP channels pathway in EA-induced antinociception in late phase of formalin test. Topical application of EA by ointment or jelly might be a useful method to relieving the inflammatory pain states.