Cholinergic-NO-cGMP mediation of sildenafil-induced antinociception.
Acetylcholine and cholinomimetic agents with predominant muscarinic action are known to increase the concentration of cGMP by activation of nitric oxide signaling pathway in the nociceptive conditions. The present study was aimed to investigate the NO-cGMP-PDE5 pathway in nociceptive conditions in the experimental animals. Nociceptive threshold was assessed by acetic acid-induced writhing assay (chemonociception) or carrageenan-induced hyperalgesia. Sildenafil [1-5 mg/kg, ip, 50-200 microg/paw, intraplantar (ipl)] produced dose dependent antinociception in both the tested models. Coadministration of acetylcholine (50 mcg/paw, ipl) or cholinomimetic agent, neostigmine (0.1 mcg/kg, ip and 25 ng/paw, ipl) augmented the peripheral antinociceptive effect of sildenafil. This effect was sensitive to blockade by L-NAME (20 mg/kg, ip, 100 microg/paw, ipl), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor, which per se had little or no effect in both the models of nociception. Further, the per se analgesic effect of acetylcholine and neostigmine was blocked by both L-NAME and methylene blue in the models of nociception, suggesting the activation of NO-cGMP pathway. Also, both L-NAME and methylene blue blocked the per se analgesic effect of sildenafil. These results indicate the peripheral accumulation of cGMP may be responsible for antinociceptive effect, and a possible interaction between cholinergic agents and PDE5 system in models of nociception.
Patil
Chandrashekhar S
CS
Pharmacology Division, University Institute of Pharmaceutical Sciences Panjab University, Chandigarh 160 014, India.
Jain
Naveen K
NK
Singh
Vijay Pal
VP
Kulkarni
Shrinivas K
SK
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism; D019342:Acetic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002351:Carrageenan / Q000494:pharmacology; D018678:Cholinergic Agents / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009388:Neostigmine / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D010147:Pain Measurement; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines; D051381:Rats; D000068677:Sildenafil Citrate; D013450:Sulfones
D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D009388:Neostigmine; D002351:Carrageenan; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse; C517384:Pde5a protein, rat; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D000109:Acetylcholine; D019342:Acetic Acid; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester