Irritable bowel syndrome (IBS) is a stress-sensitive disorder for which abdominal pain is a cardinal symptom that drives illness severity more than other motor symptoms. Early life events and female sex are risk factors for the onset and symptom exacerbation of IBS in most patients. In the somatic pain field, there is vast literature on the phenomenon named "stress-induced analgesia". This contrasts with the paucity of experimental data and knowledge on stress-induced visceral analgesia (SIVA), where there is mounting evidence that IBS patients have compromised engagement of this stress-related inhibitory descending pain modulation. We have validated a novel non-invasive technique to monitor visceral pain in rodents and uncovered that psychological stressors induces SIVA in naive rodents which is partly opiate dependent in female and opiate-independent in male rats. We also obtained preliminary data that uncovered in the colon a local CRF-proopiomelanocortin (POMC)-beta-endorphin system that is subject to upregulation by stress. Based on these novel findings, the overall objective of the proposal is to unravel the neurochemical and molecular physiological mechanisms in the brain and the colon underlying SIVA and to test the hypothesis that an early life event in the form of repeated neonatal maternal separation (MS) impairs SIVA response in adulthood. This will be achieved in three aims targeting specific pathways.
AIM 1 will characterize SIVA in adult male and female rats, naive and exposed to MS in our model of repeated water avoidance stress, delineate the neuronal substrates of SIVA in the brain and spinal cord using ?Fos? expression as long-term markers of adaptive changes with double labeling to identify chemical coding of activated neurons, and delineate the receptor subtypes and ligand mediating the naloxone-dependent component SIVA in female rats.
AIM 2 will delineate the role of key components of the stress response, the brain corticotropin releasing factor (CRF) and oxytocin signaling pathways.
AIM 3 we will unravel in the colon the functional CRF-POMC-derived peptides homolog system to the pituitary, its regulation under stress conditions, and its functionality as potential modulator of visceral pain under conditions of psychological (aim 1) vs. local immune stressors using iRNA silencing of POMC in the colon.
These aims will be achieved using pharmacological, neuroanatomical, molecular, and genetic approaches targeting the opiate, CRF and oxytocin signaling pathways along with functional studies in rats and genetically targeted mice. Overall advances in the understanding of neuronal substrata and biochemical coding of SIVA and their alterations in a model of chronic stress (MS) is of prime importance to advance understanding of physiological mechanisms underpinning SIVA. The demonstration of sex-differences in these mechanisms underlying SIVA as established in somatic pain field will highlight the importance of sex- specific interventions to modulate visceral pain that may have therapeutic significance in IBS woman patients.

Public Health Relevance

Despite continued effort, the pathophysiology of IBS is still not well understood and IBS symptoms, particularly IBS-related abdominal pain treatment, remains an unmet medical need. Similarly, while early life stress and sex differences are key factors in IBS symptom development, the link between stress or sex difference and symptoms are poorly understood. The study using rodent models proposes a new concept and novel approaches to fill the knowledge gap in the understanding of molecular mechanisms of stress-related visceral pain modulation in IBS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057238-12
Application #
8730603
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Carrington, Jill L
Project Start
1999-09-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
12
Fiscal Year
2014
Total Cost
$252,000
Indirect Cost
$52,000
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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