Lipopolysaccharide induces visceral hypersensitivity: role of interleukin-1, interleukin-6, and peripheral corticotropin-releasing factor in rats

Lipopolysaccharide (LPS) induces visceral hypersensitivity, and corticotropin-releasing factor (CRF) also modulates visceral sensation. Besides, LPS increases CRF immunoreactivity in rat colon, which raises the possibility of the existence of a link between LPS and the CRF system in modulating visceral sensation. The present study tried to clarify this possibility. Visceral sensation was assessed by abdominal muscle contractions induced by colonic balloon distention, i.e., visceromotor response, electrophysiologically in conscious rats. The threshold of visceromotor response was measured before and after administration of drugs. LPS at a dose of 1 mg/kg subcutaneously (sc) decreased the threshold at 3 h after the administration. Intraperitoneal (ip) administration of anakinra (20 mg/kg), an interleukin-1 (IL-1) receptor antagonist, or interleukin-6 (IL-6) antibody (16.6 A mu g/kg) blocked this effect. Additionally, IL-1 beta (10 A mu g/kg, sc) or IL-6 (10 A mu g/kg, sc) induced visceral allodynia. Astressin (200 A mu g/kg, ip), a non-selective CRF receptor antagonist, abolished the effect of LPS, but astressin(2)-B (200 A mu g/kg, ip), a CRF receptor type 2 (CRF2) antagonist, did not alter it. Peripheral CRF receptor type 1 (CRF1) stimulation by cortagine (60 A mu g/kg, ip) exaggerated the effect of LPS, but activation of CRF2 by urocortin 2 (60 A mu g/kg, ip) abolished it. LPS induced visceral allodynia possibly through stimulating IL-1 and IL-6 release. In addition, this effect was mediated through peripheral CRF signaling. Since the LPS-cytokine system is thought to contribute to altered visceral sensation in the patients with irritable bowel syndrome, these results may further suggest that CRF plays a crucial role in the pathophysiology of this disease.