1. Taking into consideration the effect of septic shock on releasing various mediators, the present study was undertaken in an attempt to elucidate the effect of endotoxin on naloxone-induced withdrawal contractions in the guinea-pig isolated ileum. 2. To induce withdrawal contractions, preparations removed either from saline- or endotoxin (2.5 mg/kg in 0.4 mL, i.p.)-treated animals were incubated for 5 min with morphine (40 micromol/L) and naloxone (50 micromol/L) was then applied. 3. In tissues removed from endotoxin-treated animals, a significant reduction in withdrawal contractions was observed. In control preparations, indomethacin (1 micromol/L for 15 min) significantly reduced naloxone-induced contractions, whereas N(G)-nitro-L-arginine methyl ester (L-NAME; 10 micromol/L for 15 min) had no effect. However, indomethacin pretreatment of tissues removed from endotoxin-treated animals did not modify the withdrawal contractions, whereas L-NAME pretreatment enhanced the amplitude of the withdrawal-induced contractions. 4. These results suggest that attenuation of the withdrawal contractions in guinea-pig isolated ileum induced by endotoxin-pretreatment may be due, in part, to the activation of an L-arginine-nitric oxide pathway.