Corticotropin-releasing factor receptor 1 antagonist alters regional activation
and effective connectivity in an emotional-arousal circuit during expectation of
abdominal pain.
Author(s): Hubbard CS, Labus JS, Bueller J, Stains J, Suyenobu B, Dukes GE, Kelleher DL,
Tillisch K, Naliboff BD, Mayer EA.
Affiliation(s): Center for the Neurobiology of Stress and Departments of Medicine, Physiology,
and Psychiatry, University of California, Los Angeles, Los Angeles, California
90095, USA.
Publication date & source: 2011, J Neurosci. , 31(35):12491-500
Alterations in corticotropin-releasing factor (CRF) signaling pathways have been
implicated in irritable bowel syndrome (IBS) pathophysiology. We aimed to (1)
determine the effect of the selective CRF receptor 1 antagonist (CRF(1)) GW876008
relative to placebo, on regional activation and effective connectivity of a
stress-related emotional-arousal circuit during expectation of abdominal pain
using functional magnetic resonance imaging in human subjects with a diagnosis of
IBS and healthy controls (HCs), and (2) examine GW876008 effects on state-trait
anxiety and hypothalamic-pituitary-adrenal (HPA) axis response. Although there
were no drug-related effects on peripheral HPA activity, significant central
effects were observed in brain regions associated with the stress response.
Effective connectivity analysis showed drug-induced normalizations between key
regions of the emotional-arousal circuit in patients. During pain expectation,
orally administered GW876008 relative to placebo produced significant blood
oxygen level-dependent (BOLD) signal reductions in the amygdala, hippocampus,
insula, anterior cingulate, and orbitomedial prefrontal cortices across groups.
Patients showed significantly greater BOLD responses in the left locus coeruleus
and hypothalamus after placebo compared with HCs, and BOLD signal decreases in
the left hypothalamus after drug. The inhibitory effects of GW876008 in the
hypothalamus in patients were moderated by anxiety; patients having average and
high levels of state anxiety showed drug-related BOLD decreases. GW876008
represents a novel tool for elucidating the neuronal mechanisms and circuitry
underlying hyperactivation of CRF/CRF(1) signaling and its role in IBS
pathophysiology. The unique state anxiety effects observed suggest a potential
pathway for therapeutic benefit of CRF(1) receptor antagonism for patients with
stress-sensitive disorders.
|