Send to

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

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

Author information

Gail and Gerald Oppenheimer Family Center for the Neurobiology of Stress, University of California, Los Angeles, Los Angeles, California; Department of Medicine, University of California, Los Angeles, Los Angeles, California; Department of Psychiatry, University of California, Los Angeles, Los Angeles, California.



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).


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.


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.


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.


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

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center