The aim of this study was to evaluate a possible role of nitric oxide (NO)-cyclic guanylate monophosphate (cGMP) in antinociception induced by sildenafil (phosphodiesterase–5 inhibitor), celecoxib (selective cyclooxygenase-2 inhibitor), and indomethacin (nonselective cyclooxygenase inhibitor). Each of these drugs was administered intraperitoneally into experimental mice at different doses either alone or combined with either Ng -nitro-L-arginine methyl ester hydrochloride (L-NAME, NO synthase inhibitor) or methylene blue (guanylate cyclase inhibitor). Antinociceptive activity was assessed by using a writhing test as the pain model.

The three drugs showed dose-related antinociceptive activity as defined by a reduction in writhing episodes in comparison with controls. Pretreatment of the mice with L-NAME or methylene blue led to inhibition of the antinociceptive effect of any of the three analgesic drugs tested. Ineffective doses of either celecoxib (0.5 mg/kg) or indomethacin (2.5 mg/kg) achieved significant reduction of writhing episodes when concomitantly given with sildenafil at an ineffective dose (0.5 mg/kg). This possible synergistic effect of sildenafil was inhibited when animals were pretreated with either L-NAME or methylene blue. It is concluded that NO-cGMP may play an important role in induction of analgesia by sildenafil, celecoxib, and indomethacin.