Chronic gastrointestinal (GI) symptoms, such as severe abdominal pain and diarrhea are among the most frequently reported symptoms in Veterans returning from active duty. Although little data is available for Veterans that serve in OEF/OIF, recent findings have shown that Gulf War Veterans (GWV) who develop symptoms of abdominal pain and diarrhea exhibit visceral hypersensitivity characterized by increased awareness of visceral stimuli, similar to patients with functional GI disorders such as irritable bowel syndrome (IBS). Moreover, GWV and IBS patients have higher levels of anxiety and report symptoms are worsened by stress and anxiety, suggesting a link between cognitive and peripheral autonomic activity. The objective of our study is to elucidate the specific receptor-mediated mechanism(s) by which the emotional brain communicates with the GI tract to amplify visceral pain signals. The hypothesis of this application is that specific genomic responses within the amygdala underlie the induction of anxiety and abnormal pain behaviors. The application is divided in three Specific Aims:- Under Specific Aim 1, we will attempt to identify the relative importance of amygdala glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in anxiety and visceral pain. Employing validated rodent models, that exhibit the cardinal aspects of IBS, namely anxiety accompanied by colonic hypersensitivity induced by either i) direct application of corticosterone micropellets onto the central nucleus of the amygala (CeA) or ii) repeated water avoidance stress (WAS), we will investigate whether knockdown of amygdaloid gene expression using specific antisense oligodeoxynucleotides (ODNs) inhibits the development of anxiety and pain induced by stress. For this aim the primary outcome of treatment efficacy will be changes in the behavioral measurements of anxiety and colonic hypersensitivity accompanied by decreases in gene and protein expression.
Specific Aim 2. To specifically answer the question: "What are the mechanisms responsible for the IBS-like phenotypes in rodent models of stress?" we will determine if CRF is the common downstream target of GR and MR signaling in the amygdala. To identify whether i) GR and MR regulate anxiety and hypersensitivity through a common pathway and whether ii) amygdala implants of CORT and repeated WAS use the same corticoid regulated pathway, CRF ODN will be continuously infused into the CeA of adult rats. The level of anxiety will be tested in the elevated plus maze and open field, and colonic sensitivity in response to luminal distension will be monitor a visceromotor behavioral response quantified as the number of abdominal cramps during a colonic distension Behavioral measurements will be conducted following administration of CRF OND to the CeA in the two experimental models. Under this aim we will provide novel evidence for the genomic mechanisms in the central neural circuit responsible for IBS-like phenotypes.
Specific Aim 3, we will explore the hypothesis that the bed nucleus of the stria terminalis (BNST) is part of the neuronal circuitry from the amygdala that induces anxiety and amplified visceral pain responses. The experiment proposed under this aim will provide the foundation to answer the question - do CRF2 receptors the BNSTAL play a role in the induction of anxiety and pain behaviors in response to elevated amygdala CORT. Impact on Veterans Health Care: This proposal is highly relevant to the patient-care mission of the VA since the VA cares for a population that has been exposed to severe stress, often leading to anxiety-related disorders. Successful completion of the aims proposed within this application will offer insights into the mechanisms of brain-gut dysfunction that lead to chronic abdominal pain. Our findings may identify targets for the development of novel therapeutic strategies directed at the brain, to improve the treatment or even reduce the risk for the development of anxiety-linked visceral pain in Veterans.
Many Veterans report that life stressors and negative emotions worsen or even initiate gastrointestinal symptomatology. These symptoms, including abdominal pain and abnormal bowel habits resembling those seen in patients with irritable bowel syndrome (IBS), are poorly managed and are a major cause of lost productivity in working Veterans. Successful completion of the aims proposed within this application will offer novel insights into the mechanisms of brain-gut dysfunction that lead to chronic abdominal pain. More importantly our findings may identify targets for the development of novel therapeutic strategies directed at the brain, specifically the limbic areas of the brain, to improve the treatment or even reduce the risk for th development of anxiety-linked visceral pain in Veterans. This proposal is highly relevant to the patient-care mission of the VA since the VA cares for a population that has been exposed to severe stress, often leading to anxiety-related disorders such as IBS.