Substance P and vasoactive intestinal polypeptide but not calcitonin gene-related peptide concentrations are reduced in patients with moderate and severe ulcerative colitis.

BACKGROUND AND AIMS: Ulcerative colitis is a chronic inflammatory condition characterized by an altered intestinal immunoinflammatory response. Since increasing evidence indicates that neuropeptides play a key role in the regulation of gastrointestinal immune function, the aims of this study were: a) to determine tissue and plasma levels of Vasoactive Intestinal Polypeptide, Substance P, and Calcitonin Gene-Related Peptide in patients with ulcerative colitis, and b) to ascertain whether a relationship exists between tissue concentrations of neuropeptides and the histological grading of mucosal inflammation. METHODS: A total of 29 patients with active and 39 with inactive ulcerative colitis, and 16 control subjects took part in the study. Biopsy specimens of colonic mucosa and blood samples were obtained from each subject, and neuropeptide concentrations were measured by sensitive and specific radioimmunoassays. RESULTS: Both Vasoactive Intestinal Polypeptide and Substance P concentrations were found to be significantly reduced in endoscopic biopsy specimens of patients with ulcerative colitis compared to controls (p < 0.01 and p = 0.05, respectively), and the reduction appeared to be related to the degree of mucosal inflammation; in contrast, Calcitonin Gene-Related Peptide tissue levels were unchanged. In addition, there was no significant difference in the neuropeptide plasma levels between ulcerative colitis patients and control subjects. CONCLUSIONS: Taken together, our results suggest that the reduction of Vasoactive Intestinal Polypeptide and Substance P is probably a secondary phenomenon, correlated with the degree of mucosal inflammation; whatever the mechanism, the decreased availability of these neuropeptides in the local microenvironment may play an important role in the pathogenesis of ulcerative colitis, by affecting many components of the normal immune response. Moreover, based on our data, the measurement of neuropeptide plasma concentrations does not appear to be a useful tool to monitor disease activity.

Influence of capsaicin-sensitive afferent fibers on acetic acid-induced chronic gastric ulcers in rats.

Accumulating evidence indicates that capsaicin-sensitive afferent fibers play a pivotal role in acute gastroprotection. However, whether they also influence healing of chronic gastric ulcers is still unknown. The effects of ablation of sensory neurons on acetic acid-induced chronic gastric ulcers in rats were investigated at morphologic and biochemical levels by computerized imaging analysis of the ulcerated area, histologic examination, and neuropeptide determination. Afferent nerve ablation, as a result of treating rats with a neurotoxic dose of capsaicin (50 + 50 mg/kg subcutaneously over 2 days), produced a significant increase in the ulcer area at 1 and 2 weeks after acetic acid injection. The delay in ulcer healing was associated with a marked and persistent decrease in tissue calcitonin gene-related peptide-like immunoreactivity, whereas gastric vasoactive intestinal polypeptide was unaffected by capsaicin pretreatment. Histologically, as compared with control rats, capsaicin-desensitized animals only differed in a slight increase in the inflammatory infiltrate during the early phase of ulcer formation. These findings suggest that capsaicin-sensitive afferent fibers may play a role in the healing of chronic experimental gastric ulcers in rats, but the underlying mechanisms remain to be elucidated and deserve further investigation.

Capsaicin-like effect of resiniferatoxin in the rat stomach.

Neurochemical and functional studies were performed to investigate and to compare the effects of resiniferatoxin and capsaicin in the rat stomach. Neonatal administration of resiniferatoxin (0.6-1.6 mumol/kg subcutaneously (s.c.)) produced a marked decrease in gastric calcitonin gene-related peptide-like immunoreactivity in both secretory and non-secretory region of the stomach. Almost complete depletion of the peptide was determined by neonatal administration of capsaicin (164 mumol/kg s.c.). Vasoactive intestinal polypeptide-like immunoreactivity was concomitantly unaffected by resiniferatoxin or capsaicin, thus showing the selectivity of action of the neurotoxins on gastric afferent fibers. Oral administration of an equimolar dose (0.3 nmol/kg) of resiniferatoxin or capsaicin together with 50% ethanol reduced at a similar extent gastric haemorrhagic lesions produced by the mucosal barrier-breaker agent. These findings provide evidence that resiniferatoxin and capsaicin may act on a common neuronal target in the rat stomach and that the acute exciting (protective) effect is of the same magnitude.

Gastric lesions induced by concentrated ethanol are associated with a decrease in gastric calcitonin gene-related peptide-like immunoreactivity in rats.

Gastric calcitonin gene-related peptide-like immunoreactivity (CGRP-li) was decreased in the gastric corpus of rats treated with 75% or 96% ethanol but not with 50% ethanol. The extent of gastric lesions was related to the increasing concentrations of ethanol (50-96%). CGRP-li decrease was evident already at 5 min after the 96% ethanol challenge, whereas a peptide recovery resulted 10 days after, concomitant with the healing of gastric lesions. Ethanol (96%) produced a significant decrease of CGRP-li in the whole thickness of the gastric corpus but not in the mucosal layers of the same area, indicating that the muscular layer of the gastric corpus is the zone involved in this phenomenon. Pretreatment with the selective sensory neurotoxin capsaicin induced a gastric CGRP-li decrease in the corpus and forestomach. Ethanol (96%) did not further decrease gastric corpus CGRP-li in capsaicin-pretreated rats. These findings suggest that 96% ethanol induced a decrease of CGRP-li deriving from a capsaicin-sensitive pool and that CGRP may play a role in gastric ulcer pathogenesis of haemorrhagic lesions induced by concentrated ethanol.