S U M M A R YThe aim of this study was to compare immunoreactivities for substance P with other enteric neuropeptides and GAP-43, a general marker for enteric nerves, in normal human colon and in different stages of ulcerative colitis. Tissue samples from normal colon and regions of ulcerative colitis colon were obtained at surgery and immunostained for substance P, vasoactive intestinal polypeptide (VIP), somatostatin, calcitonin gene-related peptide (CGRP), enkephalin, galanin, GAP-43, and neuron-specific enolase (NSE). Visual examination and semiquantitative analysis revealed a clear increase in the immunoreactivity for substance P in ulcerative colitis, whereas no differences were observed in the distribution of the other peptides. Therefore, quantitative analysis was performed only for substance P immunoreactivity in the lamina propria, circular muscle layer, and myenteric ganglia. In the lamina propria, the score of total intensity of substance P immunoreactivity was 0.55 Ϯ 0.15 (mean Ϯ SEM) in normal colon, 1.30 Ϯ 0.35 ( p ϭ 0.087) in least affected colon, and 2.22 Ϯ 0.28 ( p Ͻ 0.001) in moderately affected colon, whereas no significant differences were observed in immunoreactivities for GAP-43. Similar results were obtained for the mean substance P-or GAP-43-immunoreactive area. In the circular muscle layer, the number, density, total intensity, and perimeter of substance P-and GAP-43-immunoreactive fibers were essentially similar in normal colon, and in mild or moderately affected colon. We conclude that ulcerative colitis does not change the density of gut innervation as a whole. However, the density of substance P-containing nerves is specifically increased, probably due to increased peptide synthesis leading to better visibility of the fibers. U lcerative colitis (UC) is an inflammatory ulcerating process in the mucosa of colon, usually characterized by successive exacerbations and remissions of variable intensity and duration. The precise etiology of UC is unknown. Previous studies have revealed that substance P concentration is increased in inflamed colon mucosa of UC patients (Koch et al. 1987;Goldin et al. 1989). Quantitative histochemical studies indicated that this change is due to increased number of substance P-immunoreactive nerve fibers in the lamina propria (Keränen et al. 1995;Watanabe et al. 1998). It has remained unclear whether UC increases the density of enteric innervation in general and whether the increase in substance P occurs through increased intracellular peptide level, sprouting of nerve fibers, or increased number of ganglion neurons.The growth-associated protein-43 (GAP-43) is expressed by nerve fibers under conditions of embryonic growth and axon regeneration. However, GAP-43 is localized abundantly in the autonomic neurons and nerve fibers even in the mature human intestine (Sharkey et al. 1990;Vento and Soinila 1999). The expression of GAP-43 in mature intestine fits with the idea of plasticity of the enteric nervous system and represents the special nature of enteric ner...