Mediation of postprandial pancreatic enzyme secretion has been ascribed mainly to the hormone cholecystokinin (CCK) and to a vagal-vagal reflex that activate cholinergic post-ganglionic neurons in the pancreas. Recently using a rt model we have shown that does of CCK that produce physiological plasma CCK levels stimulate pancreatic enzyme secretion by acting on vagal afferent pathway. CCK-8 receptor antagonist L364,718 inhibited 75% and 80% of the pancreatic secretion stimulated by hyperosmolar NaCI solution and maltose respectively. Large amounts of 5-HT containing cells are found in the proximal duodenal area of the intestine. We hypothesize that 5-HT may be released from the EC cells lining the gut which act as a sensor to test liminal contents in response to luminal stimuli and that this interacts with the cabal afferent nerve endings in the mucosa to evoke pancreatic enzyme secretion via the vagal afferent pathway. We will demonstrate that in the anesthetized and conscious rats, liminal stimuli stimulate pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway. We plan to localize the receptive filed to the duodenal mucosa. Studies utilizing 5-HT receptor blockade and 5-HT neurotoxin will elucidate the role of mucosal released 5-HT in the mediation of these responses. To provide direct neuorphysiological evidence that luminal stimili stimulate vagal afferent pathway, unitary activities of sensory vagal neurons in response to luminal non-CCK dependent stimuli will be recorded. The role of 5-HT in mediating these responses will be investigated. The subclass of vagal afferent fibers which are sensitive to 5-HT will be identified and their sensitivity to CCK tested. Finally, we will delineate the interaction between CCK and non-CCK dependent luminal factors. These studies will have important physiological ramifications and will improve understanding of how non CCK-dependent luminal stimuli act to stimulate pancreatic enzyme secretin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051717-04
Application #
6177639
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Serrano, Jose
Project Start
1997-09-30
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$155,324
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Chen, S L; Wu, X Y; Cao, Z J et al. (2008) Subdiaphragmatic vagal afferent nerves modulate visceral pain. Am J Physiol Gastrointest Liver Physiol 294:G1441-9
Cao, Zhijun; Wu, Xiaoyin; Chen, Shengliang et al. (2008) Anterior cingulate cortex modulates visceral pain as measured by visceromotor responses in viscerally hypersensitive rats. Gastroenterology 134:535-43
Wu, Xiaoyin; Gao, Jun; Yan, Jin et al. (2008) Role for NMDA receptors in visceral nociceptive transmission in the anterior cingulate cortex of viscerally hypersensitive rats. Am J Physiol Gastrointest Liver Physiol 294:G918-27
Li, Ying (2007) Sensory signal transduction in the vagal primary afferent neurons. Curr Med Chem 14:2554-63
Gao, Jun; Wu, Xiaoyin; Owyang, Chung et al. (2006) Enhanced responses of the anterior cingulate cortex neurones to colonic distension in viscerally hypersensitive rats. J Physiol 570:169-83
Wu, X Y; Zhu, J X; Gao, J et al. (2005) Neurochemical phenotype of vagal afferent neurons activated to express C-FOS in response to luminal stimulation in the rat. Neuroscience 130:757-67
Li, Y; Wu, X Y; Owyang, C (2004) Serotonin and cholecystokinin synergistically stimulate rat vagal primary afferent neurones. J Physiol 559:651-62
Wu, Xiaoyin; Gao, Jun; Yan, Jin et al. (2004) Hypothalamus-brain stem circuitry responsible for vagal efferent signaling to the pancreas evoked by hypoglycemia in rat. J Neurophysiol 91:1734-47
Li, Ying; Wu, Xiaoyin; Zhu, Jinxia et al. (2003) Hypothalamic regulation of pancreatic secretion is mediated by central cholinergic pathways in the rat. J Physiol 552:571-87
Li, Y; Wu, X Y; Zhu, J X et al. (2001) Intestinal serotonin acts as paracrine substance to mediate pancreatic secretion stimulated by luminal factors. Am J Physiol Gastrointest Liver Physiol 281:G916-23