The hallmark symptom of irritable bowel syndrome (IBS), a chronic functional gastrointestinal (GI) disorder, is severe abdominal pain, associated with altered bowel habits, in the absence of any identifiable disease. While the cause of IBS is unknown, clinical evidence suggests a relationship between abdominal pain and stress and anxiety, suggesting a change in the brain's processing of GI signals in these patients. Using pre- clinical models, we have previously demonstrated that activation of the amygdala, an area of the brain that regulates stress and anxiety and has been identified in clinical studies, can induce anxiety and GI pain/hypersensitivity in the rat. Additionally in this animal model with IBS-like symptomatology, we then demonstrated that treating the rodents with drugs that prevented the effects of stress hormones reversed the anxiety and pain. While we have gained some insights into how the brain regulates hypersensitivity in this model, what remains unknown is "Which genes in the amygdala regulate anxiety and GI pain?" To address this question, this project will use two specific aims: 1) Investigate how stress hormone expression in the amygdala changes in an animal with induced-anxiety and GI hypersensitivity. In this aim, we will monitor both gene and protein expression in two complementary animal models, to determine which genes are responsible for the IBS-like symptoms. 2) Determine if blocking the changes in stress hormones in the amygdala prevents the development of anxiety and GI pain. In this aim, by preventing the increased gene expression in our models at the level of the amygdala, we will provide additional evidence for a central role in the co-regulation of GI hypersensitivity and anxiety. To achieve these specific aims, the mentor, Dr. Greenwood-Van Meerveld, has assembled a team of experienced collaborators to provide the trainee, Mr. Anthony C. Johnson, with the necessary tools to perform the molecular techniques necessary to monitor both total (quantitative reverse polymerase chain reaction, western blotting) and localized (in situ hybridization, immunohistochemistry) gene and protein expression. These molecular techniques will complement the training that she has provided on the behavioral measurements of anxiety and pain in IBS-like animal models. Successful completion of the experiments proposed in this project will provide additional evidence for the molecular mechanisms of stress-induced colonic hypersensitivity, providing new therapeutic targets for the treatment of IBS.

Public Health Relevance

Successful completion of the aims proposed within this application will provide evidence for the role of the amygdala in the development of colonic hypersensitivity in rats and will offer new insights into the molecular mechanisms of central sensitization that likely lead to chronic symptomatology in the irritable bowel syndrome patient population. More importantly, our findings may identify novel targets for new therapies directed at visceral pain to improve the treatment or even reduce the risk for the development of irritable bowel syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DK089871-03
Application #
8329013
Study Section
Special Emphasis Panel (ZRG1-DKUS-D (29))
Program Officer
Mcbryde, Kevin D
Project Start
2010-09-30
Project End
2013-09-29
Budget Start
2012-09-30
Budget End
2013-09-29
Support Year
3
Fiscal Year
2012
Total Cost
$26,232
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
None
Type
Other Domestic Higher Education
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Johnson, Anthony C; Greenwood-Van Meerveld, Beverley (2014) Stress-induced pain: a target for the development of novel therapeutics. J Pharmacol Exp Ther 351:327-35