The thesis of this proposal is that the release of calcitonin gene-related peptide (CGRP) and substance P (SP) from the peripheral ends of sensory nerves in the stomach wall makes a major contribution to the local regulation of gastric function. Two of the major neurotransmitters found in spinal afferents that innervate the stomach are neuropeptides. Up to 85% of spinal afferents to the stomach contain CGRP. SP is present in almost 50% of gastric spinal afferents. The proposal examines the hypothesis that the release of CGRP and SP from the peripheral ends of afferent fibers in the stomach contributes to the local regulation of gastric function and subserves an important mechanism of mucosal protection from noxious stimuli. Although CGRP and SP powerfully suppress gastric acid secretion, the precise contributions of sensory neurons to the regulation of gastric acid secretion are unknown. The mechanisms that regulate the release of CGRP and SP from nerve fibers in the stomach have not been investigated. Also unknown are the precise roles these peptides play in protection of the gastric mucosa against ulcerative agents. The four specific aims address these issues.
Specific aim I investigates the contribution of afferent neurons to the regulation of gastric acid secretion by use of the sensory neurotoxin capsaicin, in two ways: firstly, neonatal rats will be treated with capsaicin to destroy sensory neurones, and subsequently gastric function will be studied in the adult, denervated animals; secondly, gastric function will be examined in adult rats after the acute intragastric administration of capsaicin to release sensory neuropeptides in the stomach wall. Monoclonal antibodies to CGRP and SP will be used as blockers to determine the physiological role of both peptides in the control of gastric acid secretion.
Specific aim II uses monoclonal antibodies as somatostatin antagonists to examine the contribution of somatostatin to the control of gastric acid secretion and gastrin release by CGRP.
Specific aim I ll will study the regulation of CGRP and SP release from the stomach by sensitive radioimmunoassay.
Specific aim I V uses blocking antibodies to evaluate the contributions of CGRP and SP to the mechanism of mucosal protection by sensory nerves. It is anticipated that the results of the proposed experiments will provide valuable information about the control of gastric function by sensory nerves and provide an insight into the mechanism by which the gastric mucosa is protected by noxious factors in the lumen.
| Gray, J L; Bunnett, N W; Orloff, S L et al. (1994) A role for calcitonin gene-related peptide in protection against gastric ulceration. Ann Surg 219:58-64 |
| Orloff, S L; Bunnett, N W; Walsh, J H et al. (1992) Intestinal acid inhibits gastric acid secretion by neural and hormonal mechanisms in rats. Am J Physiol 262:G165-70 |
| Orloff, S L; Bunnett, N W; Wong, H et al. (1991) Neural and hormonal mechanisms mediate the enterogastric reflex: a study in intestinal transplants in rats. Gastroenterology 101:734-42 |
| Bunnett, N W; Helton, W S; Debas, H T et al. (1990) CGRP stimulates the release of pro-somatostatin-derived peptides from the gastric fundus. Am J Physiol 258:G316-9 |
| Helton, W S; Mulholland, M M; Bunnett, N W et al. (1989) Inhibition of gastric and pancreatic secretion in dogs by CGRP: role of somatostatin. Am J Physiol 256:G715-20 |
