Sildenafil produces antinociception and increases morphine antinociception in the formalin test.
The antinociceptive activity of an inhibitor of phosphodiesterase 5 alone or combined with morphine was assessed in the formalin test. Local administration of 1-[4-ethoxy-3-(6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [3, 4-d]pyrimidin-5-yl)phenylsulfonyl]-4-methyl piperazine (sildenafil, inhibitor of phosphodiesterase 5) produced a dose-dependent antinociceptive effect in the second phase of the formalin test in female Wistar rats. In contrast, morphine produced antinociception in both phases. Sildenafil significantly increased the morphine-induced antinociception. The antinociception produced by the drugs alone or combined was due to a local action, as its administration in the contralateral paw was ineffective. Pretreatment of the paws with N(G)-L-nitro-arginine methyl ester (L-NAME, nitric oxide (NO) synthesis inhibitor), 1H-[1,2, 4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor) or naloxone blocked the effect of the combination. Results suggest that opioid receptors, NO and cyclic GMP are relevant in the combination-induced antinociception. In conclusion, sildenafil produced antinociception and increased that produced by morphine, probably through the inhibition of cyclic GMP degradation.
Departamento de Farmacología y Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 22026, 14000, D.F., México, Mexico.
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Mixcoatl-Zecuatl
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Aguirre-Bañuelos
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Granados-Soto
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology; D004357:Drug Synergism; D005260:Female; D005557:Formaldehyde; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D009020:Morphine / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones
D000700:Analgesics; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D005557:Formaldehyde; D009270:Naloxone; D009020:Morphine; D000068677:Sildenafil Citrate; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester