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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

1
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.

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

PMID:
23954313
PMCID:
PMC4069031
DOI:
10.1053/j.gastro.2013.08.016
[Indexed for MEDLINE]
Free PMC Article

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