Analysis of the mechanism underlying the peripheral antinociceptive action of sildenafil in the formalin test

The mechanism of the antinociceptive action of the phosphodiesterase 5 inhibitor, sildenafil, was assessed in the formalin test. Local peripheral ipsilateral, but not contralateral, administration of sildenafil (50-200 microg/paw) produced a dose-related antinociception during both phases of the formalin test. The local peripheral pretreatment with protein kinase G inhibitor peptide (PKG inhibitor, 0.01-1 microg/paw), charybdotoxin (large- and intermediate-conductance Ca2+-activated K+ channel blocker, 0.01-1 microg/paw), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-2 microg/paw), tolbutamide (ATP-sensitive K+ channel blocker, 12.5-50 microg/paw), and tetraethylammonium (non-selective voltage-dependent K+ channel blocker, 12.5-50 microg/paw), but not 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, inhibitor of guanylyl cyclase, 12.5-50 microg/paw) or saline, significantly diminished in a dose-dependent manner sildenafil-induced local peripheral antinociception. Given alone, local peripheral administration of inhibitors did not modify formalin-induced nociceptive behavior. Results suggest that sildenafil produces its local peripheral antinociceptive effect via activation of the cyclic GMP-PKG-K+ channel pathway.