Peripheral involvement of the nitric oxide-cGMP pathway in the indomethacin-induced antinociception in rat.
The role of nitric oxide (NO) in the antinociceptive effect of indomethacin was assessed in the pain-induced functional impairment model in the rat (PIFIR model), a model of inflammatory and chronic pain similar to that observed in clinical gout. Oral administration of indomethacin (5.6 mg/kg), a nonselective cyclooxygenase inhibitor, significantly decreased the nociceptive response elicited by uric acid injected into the knee joint of the right hind limb (2.0+/-3.0 and 149.7+/-18.0 area units [au], in the absence and the presence of indomethacin, respectively). This effect of indomethacin was reduced in nearly 50% by local pretreatment with the nonselective inhibitor of NO synthase, N G-L-nitro-arginine methyl ester (L-NAME) (72.9+/-10.7 vs. 149.7+/-18.0 au, P<0.05). On the other hand, local administration of L-arginine (a NO synthase substrate) or sodium nitroprusside (a non-enzymatic NO donor) each increased in almost 40% the antinociceptive effect of indomethacin (230.9+/-12.6 and 226.6+/-9.7 vs. 149.7+/-18.0 au, P<0.05), whereas D-arginine (the inactive isomer of arginine) had no effect on the indomethacin antinociceptive response (208.0+/-34.9 vs. 149.7+/-18.0 au). These results suggest that, the antinociceptive effect of indomethacin involves, at least in part, the NO-cyclic GMP pathway at peripheral level.
Ventura-Martínez
Rosa
R
Facultad de Medicina, Departamento de Farmacología, Universidad Nacional Autónoma de México, Ciudad Universitaria Coyoacán, C.P. 04510, México, DF, México.
Déciga-Campos
Myrna
M
Díaz-Reval
Maria Irene
MI
González-Trujano
Maria Eva
ME
López-Muñoz
Francisco J
FJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism; D002908:Chronic Disease; D006152:Cyclic GMP / Q000502:physiology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006073:Gout / Q000139:chemically induced / Q000150:complications / Q000523:psychology; D007213:Indomethacin / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D009599:Nitroprusside / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects*; D017933:Peripheral Nervous System / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D014527:Uric Acid
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D014527:Uric Acid; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin