CALCITONIN-GENE-RELATED PEPTIDE MEDIATES THE PROTECTIVE EFFECT OF SENSORY NERVES IN A MODEL OF COLONIC INJURY

Recently we demonstrated that sensory denervation with the neurotoxin capsaicin worsened the inflammation in an acute and chronic model of e xperimental colitis, which suggests a protective role of sensory nerve fibers during gut inflammation. Because we could demonstrate that sen sory neuropeptides like Calcitonin gene-related peptide (CGRP) and sub stance P (SP) are released from sensory nerve fibers during intestinal inflammation, both are strong candidates as mediators for the protect ive effect of sensory neurons. In this study we investigate the role o f CGRP and SP during experimental colitis in the rat by use of recepto r antagonists against CGRP (CGRP (8-37), 1 mu g/h continuous subcutane ous infusion), SP (RP67580, a NK-1 receptor antagonist, 3 mg/kg i.p.) and an immunoneutralizingCGRP-antibody. A mild colitis was induced by a rectal enema containing trinitrobenzenesulfonic acid. The severity o f inflammation increased markedly after 7 days in the CGRP receptor an tagonist and CGRP-antibody group compared with the vehicle group as de termined by a macroscopic damage score (10.4 +/- 1.2 and 9.6 +/- 1.6 v s. 6.2 +/- 2.1) by a histologic ulceration score (82 +/- 8% and 73 +/- 6% vs. 42 +/- 23%) and by myeloperoxidase activity (19.2 +/- 6.8 and 18.1 +/- 5.9 vs. 8.6 +/- 5.3 U/mg tissue protein), respectively. Treat ment with the specific SP receptor antagonist did not significantly al ter the severity of colitis at 7 days compared with the control group. These data suggest that CGRP exerts mucosal protection during chronic experimental colitis.