title: A novel water-soluble selective CRF1 receptor antagonist, NBI 35965, blunts stress-induced visceral hyperalgesia and colonic motor function in rats.
abstract: The stress response involves the activation of two corticotropin-releasing factor (CRF) receptor subtypes. We investigated the role of CRF1 in stress-related visceral responses. A novel water-soluble tricyclic CRF1 antagonist, NBI 35965 was developed that displayed a high affinity for CRF1 (Ki approximately 4 nM) while having no binding affinity to CRF2. This antagonist also inhibited the stimulation of cAMP induced by sauvagine in CRF1 transfected cells. NBI 35965 administered per orally (p.o.) in rats (1, 3, 10 or 30 mg/kg) inhibited dose-dependently [125I]sauvagine binding selectively at brain sites of CRF1 distribution as shown by ex vivo receptor autoradiography. At the highest doses, NBI 35965 completely prevented [125I]sauvagine labeling in the cortex. NBI 35965 (10 mg/kg) administered p.o. or subcutaneously (s.c.) 1 h before intravenous CRF completely blocked the 81% shortening of distal colonic transit time induced by CRF. NBI 35965 (20 mg/kg s.c.) significantly reduced the defecation in response to water avoidance stress but not that induced by s.c. carbachol. In adult male Long-Evans rats that had undergone maternal separation, acute water avoidance stress significantly increased the visceromotor response to colorectal distention (20-80 mmHg) by 42+/-19% compared with the response before stress. Stress-induced visceral hyperalgesia was abolished by NBI 35965 (20 mg/kg, s.c.). The data show that NBI 35965 is a novel water-soluble selective CRF1 antagonist with bioavailability to the brain upon peripheral administration and that CRF1 receptor signaling pathways are involved in water avoidance stress-induced hyperalgesia to colorectal distention and stimulation of colonic transit.
authors.affiliation: CURE/Digestive Diseases Research Center and Center for Neurovisceral Sciences and Women's Health (CNS), West Los Angeles VA Medical Center, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90073, USA. mmuluget@ucla.edu
authors.forename: Mulugeta
authors.initials: M
authors.lastname: Million
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Grigoriadis
authors.forename: Sue
authors.initials: S
authors.lastname: Sullivan
authors.forename: Paul D
authors.initials: PD
authors.lastname: Crowe
authors.forename: James A
authors.initials: JA
authors.lastname: McRoberts
authors.forename: Huping
authors.initials: H
authors.lastname: Zhou
authors.forename: Paul R
authors.initials: PR
authors.lastname: Saunders
authors.forename: Celine
authors.initials: C
authors.lastname: Maillot
authors.forename: Emeran A
authors.initials: EA
authors.lastname: Mayer
authors.forename: Yvette
authors.initials: Y
authors.lastname: Taché
mesh_terms: D029845:Amphibian Proteins; D000818:Animals; D001345:Autoradiography; D016466:CHO Cells; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D003672:Defecation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005772:Gastrointestinal Transit / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D008426:Maternal Deprivation; D036361:Peptide Hormones; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013312:Stress, Physiological; D014162:Transfection; D014665:Vasodilator Agents / Q000494:pharmacology; D014781:Viscera / Q000187:drug effects / Q000502:physiology; D014867:Water; D000099052:CRF Receptor, Type 1
chemical_list: D029845:Amphibian Proteins; D036361:Peptide Hormones; D010455:Peptides; D018019:Receptors, Corticotropin-Releasing Hormone; D014665:Vasodilator Agents; D014867:Water; D000099052:CRF Receptor, Type 1; C025727:sauvagine; D000242:Cyclic AMP