Metformin and phenformin block the peripheral antinociception induced by diclofenac and indomethacin on the formalin test.
OBJECTIVE
Recent evidence has shown that systemic administration of sulfonylureas and biguanides block the diclofenac-induced antinociception, but not the effect produced by indomethacin. However, there are no reports about the peripheral interaction between analgesics and the biguanides metformin and phenformin. Therefore, this work was undertaken to determine whether glibenclamide and glipizide and the biguanides metformin and phenformin have any effect on the peripheral antinociception induced by diclofenac and indomethacin.


METHODS
Diclofenac and indomethacin were administered locally in the formalin-injured rat paw, and the antinociceptive effect was evaluated using the 1% formalin test. To determine whether peripheral antinociception induced by diclofenac or indomethacin was mediated by either the ATP-sensitive K(+) channels or biguanides-induced mechanisms, the effect of pretreatment with the appropriates vehicles or glibenclamide, glipizide, metformin and phenformin on the antinociceptive effect induced by local peripheral diclofenac and indomethacin was assessed.


RESULTS
Local peripheral injections of diclofenac (50-200 μg/paw) and indomethacin (200-800 μg/paw) produced a dose-dependent antinociception during the second phase of the test. Local pretreatment with glibenclamide, glipizide, metformin and phenformin blocked the diclofenac-induced antinociception. On the other hand, the pretreatment with glibenclamide and glipizide did not prevent the local antinociception produced by indomethacin. Nonetheless, metformin and phenformin reversed the local antinociception induced by indomethacin.


CONCLUSIONS
Data suggest that diclofenac could activate the K(+) channels and biguanides-dependent mechanisms to produce its peripheral antinociceptive effects in the formalin test. Likewise, a biguanides-dependent mechanism could be activated by indomethacin consecutively to generate its peripheral antinociceptive effect.
Laboratorio de Farmacología, Área Académica de Medicina del Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Eliseo Ramírez Ulloa 400, Col. Doctores, Pachuca, Hgo., 42090, Mexico. mario_i_ortiz@hotmail.com
Mario I
MI
Ortiz
D000818:Animals; D004008:Diclofenac / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D010629:Phenformin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D054086:KATP Channels; D004008:Diclofenac; D008687:Metformin; D010629:Phenformin; D007213:Indomethacin