title: Corticotropin-releasing factor receptor 1 antagonist alters regional activation and effective connectivity in an emotional-arousal circuit during expectation of abdominal pain.
abstract: 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.
authors: Center for the Neurobiology of Stress and Departments of Medicine, Physiology, and Psychiatry, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors: Catherine S
authors: CS
authors: Hubbard
authors: Jennifer S
authors: JS
authors: Labus
authors: Joshua
authors: J
authors: Bueller
authors: Jean
authors: J
authors: Stains
authors: Brandall
authors: B
authors: Suyenobu
authors: George E
authors: GE
authors: Dukes
authors: Dennis L
authors: DL
authors: Kelleher
authors: Kirsten
authors: K
authors: Tillisch
authors: Bruce D
authors: BD
authors: Naliboff
authors: Emeran A
authors: EA
authors: Mayer
mesh_terms: D015746:Abdominal Pain / Q000150:complications / Q000473:pathology / Q000523:psychology; D000284:Administration, Oral; D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D001931:Brain Mapping; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009434:Neural Pathways / Q000098:blood supply; D010100:Oxygen / Q000097:blood; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D011720:Pyrazoles / Q000627:therapeutic use*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013315:Stress, Psychological / Q000188:drug therapy* / Q000209:etiology*; D055815:Young Adult; D000099052:CRF Receptor, Type 1
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C552097:GW 876008; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D010100:Oxygen