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

Gastroenterology. 2013 Dec;145(6):1253-61.e1-3. doi: 10.1053/j.gastro.2013.08.016. Epub 2013 Aug 14.

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.

Keywords: AMYG; BOLD; CRF-R1; Corticotropin-Releasing Factor Receptor 1 (CRF-R1) Antagonist; Extinction; Fear Conditioning; HCs; HIPP; HYPO; IBS; LCC; PLA; SCR; SNS; THAL; aINS; aMCC; amygdala; anterior insula; anterior midcingulate cortex; blood-oxygen level−dependent; corticotropin-releasing factor receptor 1; dlPFC; dorsolateral prefrontal cortex; healthy controls; hippocampus; hypothalamus; irritable bowel syndrome; locus coeruleus complex; mPFC; medial prefrontal cortex; pACC; placebo; pregenual anterior cingulate cortex; skin conductance responses; sympathetic nervous system; thalamus; ventrolateral prefrontal cortex; vlPFC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Abdominal Pain / physiopathology
  • Abdominal Pain / psychology
  • Adult
  • Anxiety Disorders / physiopathology*
  • Anxiety Disorders / 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
  • Fear / psychology
  • Female
  • Galvanic Skin Response / drug effects
  • Galvanic Skin Response / physiology
  • Humans
  • Irritable Bowel Syndrome / physiopathology*
  • Middle Aged
  • Pyrazoles / pharmacology
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors
  • Receptors, Corticotropin-Releasing Hormone / drug effects
  • Receptors, Corticotropin-Releasing Hormone / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*

Substances

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