Participation of the nitric oxide-cyclic GMP-ATP-sensitive K(+) channel pathway in the antinociceptive action of ketorolac.
The involvement of nitric oxide (NO), cyclic GMP and ATP-sensitive K(+) channels in the antinociceptive effect of ketorolac was assessed using the formalin test in the rat. Local administration of ketorolac in a formalin-injured paw produced a dose-dependent antinociceptive effect due to a local action, as drug administration in the contralateral paw was ineffective. Pretreatment of the injured paw with N(G)-L-nitro-arginine methyl ester (L-NAME, an NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor) or glibenclamide (an ATP-sensitive K(+) channel blocker) prevented ketorolac-induced antinociception. However, pretreatment with saline or N(G)-D-nitro-arginine methyl ester (D-NAME) did not block antinociception. Local administration of S-nitroso-N-acetylpenicillamine (SNAP, an NO donor) was inactive by itself, but increased the effect of ketorolac. The present results suggest that the antinociceptive effect of ketorolac involves activation of the NO-cyclic GMP pathway, followed by an opening of ATP-sensitive K(+) channels at the peripheral level.
Lázaro-Ibáñez
G G
GG
Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México, D.F., Mexico.
Torres-López
J E
JE
Granados-Soto
V
V
D000255:Adenosine Triphosphate / Q000502:physiology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020910:Ketorolac / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D010147:Pain Measurement; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000700:Analgesics; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D015221:Potassium Channels; D011810:Quinoxalines; C110881:S-nitro-N-acetylpenicillamine; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D010396:Penicillamine; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester; D020910:Ketorolac