Sildenafil-induced peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway

Although several lines of evidence have shown a role of the nitric oxide/cy clic guanosine monophosphate signaling pathway in the nociceptive mechanism , the exact role of the phosphodiesterase (PDE) 5 enzyme via the NO-cGMP pa thway is not fully understood in pain response. The present study was aimed at exploring the role of the NO-cGMP pathway in nociceptive conditions in experimental animals. Peripheral nociception was assessed by acetic acid-in duced chemonociception or carrageenan-induced hyperalgesia and central noci ception was assessed by tail-flick and hot-plate methods. Sildenafil exhibi ted dose-dependent (1, 2, 5 and 10 mg/kg, i.p.) antinociception in both mal e and female mice against acetic acid-induced writhing. However, it did not alter the pain threshold in central nociception (5 and 10 mg/kg, i.p.). Lo cal administration of sildenafil (50-200 mug/paw, i.pl) also attenuated car rageenan-induced hyperalgesia, In the peripheral nociceptive reaction (acet ic acid-induced chemonociception), the antinociceptive effect of sildenafil (2 mg/kg, i.p.) was enhanced by co-administration of sodium nitroprusside (0.25 mg/kg), and F-arginine (50 mg/kg). Sildenafil-induced analgesia was s ignificantly blocked by methylene blue (1 mg/kg), a guanylate cyclase inhib itor, but was not reversed by L-NAME (10 mg/k.g), a nitric oxide synthase i nhibitor. But a higher dose of L-NAME (20 mg/kg) significantly reversed sil denafil analgesia. Both of these agents also reversed the facilitatory effe ct of L-arginine (50 mg/kg) and sodium nitroprusside (0.25 mg/kg) on silden afil analgesia. These results suggest that sildenafil-induced analgesia is mediated via the inhibition of PDE5. The results also indicate that the gua nylate cyclase system is stimulated in the peripheral nociceptive reaction. In conclusion, sildenafil produces antinociception and its effect can be p otentiated by sodium nitroprusside and L-arginine, probably through the act ivation of the NO-cyclic GMP pathway. (C) 2001 Elsevier Science B.V. All ri ghts reserved.