This study investigated the mechanisms involved in the antinociceptive action induced by diphenyl diselenide ((PhSe)(2)) in the formalin test. Mice were pre-treated with (PhSe)(2) by the oral route (0.1-100 mg kg(-1)), 30 min before formalin injection. To address some of the mechanisms by which (PhSe)(2) inhibits formalin-induced nociception mice were treated with different drugs. The antinociceptive effect of (PhSe)(2) was shown in the first and second phases of the formalin test. The antinociceptive effect caused by (PhSe)(2) (10 mg kg(-1), p.o.) was prevented by intrathecal injection of K(+) channel blockers such as apamin and charybdotoxin (small- and large-conductance Ca(2+)-activated K(+) channel inhibitors, respectively) and tetraethylammonium (TEA, a non-selective voltage-dependent K(+) channel inhibitor), but not glibenclamide (an ATP-sensitive K(+) channel inhibitor). The antinociceptive action caused by (PhSe)(2) (10 mg kg(-1), p.o.) was also blocked by a nitric oxide (NO) synthase inhibitor (N(omega)-nitro-L-arginine, L-NOARG) and the soluble guanylate cyclase inhibitors 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and methylene blue. These results suggest the participation of NO/cyclic GMP/Ca(2+) and K(+) channel pathways in the antinociceptive effect caused by (PhSe)(2).