Impaired emotional learning and involvement of the corticotropin-releasing factor signaling system in patients with irritable bowel syndrome.

Abstract

BACKGROUND & AIMS:

Alterations in central corticotropin-releasing factor signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We aimed to characterize the effects of the corticotropin-releasing factor receptor 1 (CRF-R1) antagonist, GW876008, on brain and skin conductance responses during acquisition and extinction of conditioned fear to the threat of abdominal pain in subjects with IBS and healthy individuals (controls).

METHODS:

We performed a single-center, randomized, double-blind, 3-period crossover study of 11 women with IBS (35.50 ± 12.48 years old) and 15 healthy women (controls) given a single oral dose (20 mg or 200 mg) of the CRF-R1 antagonist or placebo. Blood-oxygen level-dependent responses were analyzed using functional magnetic resonance imaging in a tertiary care setting.

RESULTS:

Controls had greater skin conductance responses during acquisition than extinction, validating the fear-conditioning paradigm. In contrast, during extinction, women with IBS had greater skin conductance responses than controls-an effect normalized by administration of a CRF-R1 antagonist. Although the antagonist significantly reduced activity in the thalamus in patients with IBS and controls during acquisition, the drug produced greater suppression of blood-oxygen level-dependent activity in a wide range of brain regions in IBS patients during extinction, including the medial prefrontal cortex, pons, hippocampus, and anterior insula.

CONCLUSIONS:

Although CRF signaling via CRF-R1 is involved in fear acquisition and extinction learning related to expected abdominal pain in patients with IBS and controls, this system appears to be up-regulated in patients with IBS. This up-regulation might contribute to the previously reported abnormal brain responses to expected abdominal pain.

• Authors: Jennifer S Labus, Catherine S Hubbard, Joshua Bueller, Bahar Ebrat, Kirsten Tillisch, Michelle Chen, Jean Stains, George E Dukes, Dennis L Kelleher, Bruce D Naliboff, Michael Fanselow, Emeran A Mayer
• Journal: Gastroenterology (Gastroenterology) Vol. 145 Issue 6 Pg. 1253-61.e1-3 (Dec 2013) ISSN: 1528-0012 [Electronic] United States
• PMID: 23954313 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• GW 876008
• Pyrazoles
• Receptors, Corticotropin-Releasing Hormone
• CRF receptor type 1
• Corticotropin-Releasing Hormone

Topics

• Abdominal Pain (physiopathology, psychology)
• Adult
• Anxiety Disorders (physiopathology, psychology)
• Brain (physiology)
• Brain Mapping
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Corticotropin-Releasing Hormone (physiology)
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Double-Blind Method
• Extinction, Psychological (physiology)
• Fear (physiology, psychology)
• Female
• Galvanic Skin Response (drug effects, physiology)
• Humans
• Irritable Bowel Syndrome (physiopathology)
• Middle Aged
• Pyrazoles (pharmacology)
• Receptors, Corticotropin-Releasing Hormone (antagonists & inhibitors, drug effects, physiology)
• Signal Transduction (drug effects, physiology)