Modulatory effect of cyclooxygenase inhibitors on sildenafil-induced antinociception.
Peripheral activation of the NO-cGMP pathway has been implicated in various nociceptive conditions. The antinociceptive effect of the PDE-5 inhibitor, sildenafil, alone or in combination with cyclooxygenase inhibitor diclofenac and nimesulide, was assessed in the different animal models of peripheral nociception. In the present study we investigated the possible interaction between cyclooxygenase and NO-cGMP pathway in writhing assay and carrageenan-induced hyperalgesia in mice and rats, respectively. Sildenafil [1-2 mg/kg, i.p. or 50-100 microg/paw, intraplantar (i.pl.)], nimesulide (1-2 mg/kg, i.p. or 25-50 microg/paw, i.pl.) and diclofenac (1-2 mg/kg, i.p. or 25-50 microg/paw, i.pl.) exhibited an antinociceptive effect in both the models. When ineffective doses of sildenafil (0.5 mg/kg, i.p and 25 microg/paw, i.pl.) were co-administered with ineffective doses of nimesulide (0.5 mg/kg, i.p. and 10 microg/paw, i.pl.) and diclofenac (0.5 mg/kg, i.p. and 10 microg/paw, i.pl.), there was a significant increase in the antinociceptive effect in both the models of peripheral nociception. Further, the potentiation of the effect was blocked by L-NAME (20 mg/kg, i.p., 100 microg/paw, i.pl.), a non-selective NOS inhibitor and methylene blue (1 mg/kg, i.p.), a guanylate cyclase inhibitor. L-NAME or methylene blue itself had little or no effect on both the models of hyperalgesia. These results suggest that cyclooxygenase, NO and cGMP are relevant in the combination-induced antinociception. In conclusion, sildenafil induced antinociception, and its potentiation of the effect of the cyclooxygenase inhibitors nimesulide and diclofenac was probably mediated through the activation of the NO-cGMP pathway and inhibition of cyclic GMP degradation.
Patil
Chandrashekhar S
CS
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Punjab, India.
Jain
Naveen K
NK
Singh
Amarjit
A
Kulkarni
Shrinivas K
SK
D000818:Animals; D002351:Carrageenan / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D006152:Cyclic GMP / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004008:Diclofenac / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D013450:Sulfones
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D004008:Diclofenac; D002351:Carrageenan; D000068677:Sildenafil Citrate; D006152:Cyclic GMP; C012655:nimesulide; D019331:NG-Nitroarginine Methyl Ester