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 μg/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 μg/paw), charybdotoxin (large- and intermediate-conductance Ca 2 +-activated K + channel blocker, 0.01–1 μg/paw), apamin (small-conductance Ca 2 +-activated K + channel blocker, 0.1–2 μg/paw), tolbutamide (ATP-sensitive K + channel blocker, 12.5–50 μg/paw), and tetraethylammonium (non-selective voltage-dependent K + channel blocker, 12.5–50 μg/paw), but not 1 H-(1,2,4)-oxadiazolo(4,2- a)quinoxalin-1-one (ODQ, inhibitor of guanylyl cyclase, 12.5–50 μg/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.