Nitric oxide reverses endotoxin-induced inflammatory hyperalgesia via inhibition of prostacyclin production in mice

We examined whether nitric oxide (NO), derived from constitutive NO synthase (NOS) and/or inducible NOS (iNOS), could contribute to endotoxin-induced inflammatory hyperalgesia via interacting with nuclear factor-κB (NF-κB), inducible cyclooxygenase (COX-2) and/or polyADP-ribose synthase (PARS). Injection of endotoxin (10 mg kg−1, i.p.) to mice elicited hyperalgesia, determined by hot plate test, which is prevented by NO precursor (l-arginine), cNOS/iNOS inhibitor (NG-nitro-l-arginine methyl ester; l-NAME), NF-κB inhibitor (N-acetylserotonin), COX inhibitor (indomethacin), COX-2 inhibitor (DFU) and PARS inhibitor (3-aminobenzamide). Endotoxin caused a decrease in serum nitrite levels prevented by N-acetylserotonin, l-arginine, indomethacin, DFU or 3-aminobenzamide. Endotoxin increased serum 6-keto-PGF1α levels diminished by l-arginine or aminoguanidine (iNOS inhibitor). l-Arginine, l-NAME, aminoguanidine, DFU or 3-aminobenzamide prevented endotoxin-induced decrease in heart, lungs, kidneys and brain nitrite and malonedialdehyde levels and myeloperoxidase activity. In conclusion, NO reverses endotoxin-induced inflammatory hyperalgesia via inhibition of prostacyclin production, and also contributes to the analgesic effect of NF-κB, COX or PARS inhibitors.