Central Mechanisms Modulating Visceral Sensitivity


Principal Investigator: Beverley Greenwood-Van Meerveld
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2013-04-01 - 2017-03-31
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. Understanding Pain of Gastrointestinal Origin in Women that Serve in OEF/OIF
    Beverley Greenwood-Van Meerveld; Fiscal Year: 2013
    ..Moreover, we will examine whether rats exposed to ELS show altered behavioral responses to chronic stress in adulthood compared to age-matched controls ..
  2. Molecular and Epidemiologic Basis of UTI in Women
    Scott J Hultgren; Fiscal Year: 2013
    ..DESCRIPTION (provided by applicant): Not provided ..
  3. Prepubertal Stress, Windows of Risk &Sex Bias for Affective Disturbance
    C NEILL NEILL EPPERSON; Fiscal Year: 2013
    ..The Center would provide an intellectual platform with important resources to encourage established investigators, and their mentees, to consider sex and gender as crucial factors in their research. ..
  4. Enduring Effects of Early-Life Serotonin Signaling
    Randy D Blakely; Fiscal Year: 2013
    ..abstract_text> ..
  5. Effects of an angiotensin ll antagonist in a rat model of insomnia
    Georgina Cano; Fiscal Year: 2013
    ..Our goal is to find a pharmacologic treatment for insomnia that restores natural sleep and minimizes side-effects by acting on more specific brain targets. ..
  6. North American Mitochondrial Disease Consortium (NAMDC)
    JOHN L THOMPSON; Fiscal Year: 2013
  7. Methamphetamine Abuse Research Center
    AARON J JANOWSKY; Fiscal Year: 2013
    ..Data and samples are shared and compared across components. Thus, the MARC addresses clinically relevant themes using integrated, innovative, multidisciplinary, and translational approaches. ..
  8. Mechanisms underlying TMD-IBS comorbidity
    Richard J Traub; Fiscal Year: 2013
    ..Either result will guide future studies into mechanisms underlying comorbid pain conditions. ..
    W Allan Walker; Fiscal Year: 2013
    ..abstract_text> ..
  10. Novel Mechanisms of NSAID Action in Alzheimer's Disease
    Edward H Koo; Fiscal Year: 2013
    ..By providing additional preclinical and clinical information on GAMs, such studies should contribute significantly to the further development of GSMs as Alzheimer's therapeutics. ..
  11. Neuroimaging Acupuncture Effects Brain Activity in Chronic low Back Pain
    Bruce R Rosen; Fiscal Year: 2013
    ..Understanding the neural influence of somatosensation on acupuncture placebo effects will significantly impact our understanding of acupuncture and allow for development of more inert acupuncture placebos. ..
  12. Defining and Treating Written Language Disabilities
    VIRGINIA WISE BERNINGER; Fiscal Year: 2013
    ..The proposed multidisciplinary research has practical significance for improving diagnosis and providing more effective services which may lower such risks. ..
    Margaret McLean Heitkemper; Fiscal Year: 2013
    ..Results will lead to greater understanding of the underlying mechanisms accounting for chronic symptom reports as well as examine an endophenotype within a common heterogeneous condition, IBS. ..
  14. Cardiovascular disease, depression, and oxytocin
    MELISSA SCOTTI; Fiscal Year: 2013
    ..abstract_text> ..
  15. Spinal glia activation in chronic stress-induced visceral hyperalgesia
    Sylvie Bradesi; Fiscal Year: 2013
  16. Opposing Effects of Chronic Stress on Amygdala and Hippocampus
    Ki Ann Goosens; Fiscal Year: 2013
    ..This is particularly important as chronic stress is a potent trigger for affective mental illnesses such as post-traumatic stress disorder (PTSD), but the mechanisms by which stress triggers this class of mental illnesses is unknown. ..
  17. Alzheimer's Disease Research Center
    Douglas R Galasko; Fiscal Year: 2013
    ..It will provide an environment and core resources to enhance research, foster professional and community training, and coordinate interdisciplinary research. ..
  18. Neural Sensitivity to Stress During Drug Withdrawal
    Gina L Forster; Fiscal Year: 2013
  19. Molecular Biology and Genetics of Human Tumor Viruses
    Paul F Lambert; Fiscal Year: 2013
    ..abstract_text> ..
  20. Modulation of Colonic Epithelial Permeability by Sex Hormones
    Muriel Larauche; Fiscal Year: 2013
    ..and secretion in IBS and enable the candidate to propose new testable hypotheses regarding mechanisms of IBS pain and constipation, in particular regarding differential treatment approaches based on pathophysiology and sex differences ..
  21. Chronic Stress and Abdominal Pain: Novel Mechanisms
    John W Wiley; Fiscal Year: 2013
  22. Synaptic Changes by Stress in Prefrontal Cortex
    Zhen Yan; Fiscal Year: 2013