Participation of the L-arginine-nitric oxide-cyclic GMP-ATP-sensitive K+ channel cascade in the antinociceptive effect of rofecoxib.
The antinociceptive effect of rofecoxib, a preferential inhibitor of cyclooxygenase-2, was assessed in the pain-induced functional impairment model in the rat. Systemic administration of rofecoxib generated a dose-dependent antinociceptive effect in rats injected with uric acid into the knee joint of the right hindlimb in order to produce nociception. Ipsilateral intra-articular pretreatment with N(G)-L-nitro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide (NO) synthesis), 1H-(1,2,4)-oxadiazolo (4,2-a)quinoxalin-1-one (ODQ, an inhibitor soluble guanylyl cyclase), and the ATP-sensitive potassium channel blocker glibenclamide reversed the antinociceptive effect of rofecoxib p.o. However, ipsilateral intra-articular pretreatment with L-arginine (a NO substrate), or 3-morpholino-sydnonimine-HCl (SIN-1, a non-enzymatic donor of NO), potentiated the antinociceptive effect induced by rofecoxib. The present results suggest that, in addition to cyclooxygenase-2 inhibition, the antinociceptive effect of rofecoxib could also involve activation of the L-arginine-NO-cyclic GMP (cGMP) pathway, followed by opening of ATP-sensitive K+ channels at the peripheral level.
Déciga-Campos
Myrna
M
Laboratorio No. 7, Dolor y Analgesia del Departamento de Farmacobiología, CINVESTAV-IPN, Calzada de los Tenorios No. 235 Col. Granjas Coapa, Deleg. Tlálpan, Mexico, DF, CP 14330, Mexico.
López-Muñoz
Francisco J
FJ
D000255:Adenosine Triphosphate / Q000502:physiology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007783:Lactones / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013450:Sulfones
D000700:Analgesics; D004791:Enzyme Inhibitors; D007783:Lactones; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013450:Sulfones; C116926:rofecoxib; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D001120:Arginine; D006152:Cyclic GMP