Cholinergic-NO-cGMP mediation of sildenafil-induced antinociception

Abstract

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 [1-5mg/kg, ip, 50-200 μg/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 μg/paw<i>, </i>ipl), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor,which <i>per se </i>had little or no effect in both the models of nociception. Further, the <i>per se </i>analgesic effect of acetylcholine and neostigmine was blocked by both L-NAME and methylene blue in the models of nociception, suggesting the activation of NOcGMP pathway. Also, both L-NAME and methylene blue blocked the <i>per se </i>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.