The gastro-intestinal tract is highly innervated by both intrinsic and extrinsic sensory nerves and this neuronal component is thought to play a role in local inflammatory responses. This in vivo study was designed to determine the function of
substance P and the
tachykinin NK1 receptor in the pathogenesis of
inflammatory bowel disease by the use of the specific antagonist
RP 67580. The
dinitrofluorobenzene (
DNFB)-induced colonic
hypersensitivity model is associated with increased levels of
substance P in the colon. The
tachykinin NK1 receptor antagonist
RP 67580 was used to investigate the role of
substance P on the development of
diarrhea, mast cell infiltration and activation, colonic tissue damage,
hypertrophy of colonic lymphoid structures and leukocyte infiltration. The formation of watery
diarrhea could completely be abrogated by treatment with
RP 67580 in
DNFB-sensitized animals 72 h after challenge. Antagonizing the
tachykinin NK1 receptor in these animals also resulted in significantly reduced colonic patch
hypertrophy, leukocyte recruitment and tissue damage. Total levels of
substance P in the colon of
DNFB-sensitized mice treated with the inactive enantiomer of the
tachykinin NK1 receptor antagonist were significantly higher compared to
DNFB-sensitized mice treated with
RP 67580 72 h after challenge. Although
RP 67580 was capable of reducing the total number of mast cells present in the colon, mast cell activation was not affected by this treatment. In conclusion, in this chemically-induced immunological model for
inflammatory bowel disease we demonstrated an important role for
tachykinin NK1 receptors, and its
ligand substance P, in the development of
colitis downstream from mast cell activation.