title: A corticotropin-releasing factor receptor antagonist improves urodynamic dysfunction produced by social stress or partial bladder outlet obstruction in male rats.
abstract: Barrington's nucleus, in the pons, regulates micturition through spinal projections to preganglionic parasympathetic neurons. The stress neuropeptide CRF is prominent in these projections and has an inhibitory influence. Social stress in rats causes urinary retention and abnormal urodynamics resembling those produced by partial bladder outlet obstruction (pBOO), and this is associated with CRF upregulation in Barrington's nucleus. Here, we examined the role of CRF in social stress- and pBOO-induced urodynamic dysfunction by assessing the ability of a CRF₁ receptor antagonist to alter these effects. Male rats exposed to repeated resident-intruder stress were administered vehicle or a CRF₁ antagonist (NBI-30775) daily prior to the stress. Urodynamic function was recorded in the unanesthetized state 72 h after the final stress. NBI-30775 prevented the increased intermicturition interval, micturition volume, and bladder capacity produced by social stress, but not the increase in CRF expression in Barrington's nucleus neurons. The urinary dysfunction was also partly prevented by shRNA targeting of CRF in Barrington's nucleus, suggesting that stress-induced urinary dysfunction results, in part, from CRF upregulation in Barrington's nucleus and enhanced postsynaptic effects in the spinal cord. Finally, NBI-30775 improved urodynamic function of rats that had pBOO of 2-wk duration when administered daily during the second week but did not block the increase in CRF expression in Barrington's nucleus neurons. These findings implicate a role for Barrington's nucleus CRF in stress- and pBOO-induced urodynamic changes and suggest that CRF₁ antagonists may be useful therapeutic agents for the treatment of urinary dysfunction.
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Wood
authors.forename: Kile
authors.initials: K
authors.lastname: McFadden
authors.forename: Tagan
authors.initials: T
authors.lastname: Griffin
authors.forename: John H
authors.initials: JH
authors.lastname: Wolfe
authors.forename: Stephen
authors.initials: S
authors.lastname: Zderic
authors.forename: Rita J
authors.initials: RJ
authors.lastname: Valentino
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis; D000229:Dependovirus / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors; D008297:Male; D011149:Pons / Q000502:physiology; D011743:Pyrimidines / Q000627:therapeutic use*; D012313:RNA / Q000032:analysis / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012931:Social Environment; D013315:Stress, Psychological / Q000523:psychology / Q000652:urine*; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy* / Q000503:physiopathology; D014563:Urodynamics / Q000187:drug effects*
chemical_list: D011743:Pyrimidines; C412383:R 121919; D034741:RNA, Small Interfering; D018019:Receptors, Corticotropin-Releasing Hormone; D012313:RNA; D003346:Corticotropin-Releasing Hormone
keywords: Barrington's nucleus; cystometry; resident-intruder; urinary
references.citation: Biol Psychiatry. 2012 Feb 15;71(4):317-26
references.pmid: 21783178
references.citation: J Psychiatr Res. 2003 Nov-Dec;37(6):525-33
references.pmid: 14563384
references.citation: Am J Physiol Regul Integr Comp Physiol. 2006 Jun;290(6):R1697-706
references.pmid: 16439667
references.citation: Am J Physiol Regul Integr Comp Physiol. 2006 Sep;291(3):R692-703
references.pmid: 16614059
references.citation: J Comp Neurol. 1987 Jun 8;260(2):256-98
references.pmid: 3497182
references.citation: J Neuroendocrinol. 2006 Jan;18(1):13-24
references.pmid: 16451216
references.citation: Auton Neurosci. 2005 Dec 30;123(1-2):26-35
references.pmid: 16256445
references.citation: J Virol. 2003 Jun;77(12):7034-40
references.pmid: 12768022
references.citation: Contrib Nephrol. 1982;30:38-42
references.pmid: 6126316
references.citation: Neuroendocrinology. 1983;36(3):165-86
references.pmid: 6601247
references.citation: J Pharmacol Exp Ther. 2003 Feb;304(2):874-80
references.pmid: 12538845
references.citation: Horm Behav. 2003 Jan;43(1):158-65
references.pmid: 12614646
references.citation: Brain Res. 1989 Jul 17;492(1-2):99-115
references.pmid: 2752312
references.citation: Brain Res. 1979 Aug 31;172(3):533-8
references.pmid: 476495
references.citation: Am J Physiol Regul Integr Comp Physiol. 2009 May;296(5):R1671-8
references.pmid: 19279290
references.citation: Neuropsychopharmacology. 2002 Aug;27(2):194-202
references.pmid: 12093593
references.citation: J Neurosci. 1999 Aug 1;19(15):6684-93
references.pmid: 10414997
references.citation: J Urol. 2003 Aug;170(2 Pt 1):476-9
references.pmid: 12853803
references.citation: Endocrinology. 2010 Apr;151(4):1795-805
references.pmid: 20160137
references.citation: J Comp Neurol. 1996 Oct 14;374(2):161-79
references.pmid: 8906491
references.citation: Nat Rev Urol. 2011 Jan;8(1):19-28
references.pmid: 21135878
references.citation: Am J Physiol Renal Physiol. 2009 Oct;297(4):F1101-8
references.pmid: 19587139
references.citation: Eur J Neurosci. 2003 Dec;18(12):3311-24
references.pmid: 14686904
references.citation: Psychopharmacology (Berl). 1979 Feb 28;60(3):253-9
references.pmid: 108702
references.citation: Brain Res. 1996 Sep 2;732(1-2):1-15
references.pmid: 8891263
references.citation: Neurosci Lett. 1995 Aug 25;196(3):185-8
references.pmid: 7501279
references.citation: Curr Drug Targets CNS Neurol Disord. 2002 Oct;1(5):467-93
references.pmid: 12769601
references.citation: Physiol Behav. 1999 Nov;67(5):769-75
references.pmid: 10604849
references.citation: J Comp Neurol. 1995 May 15;355(4):629-40
references.pmid: 7636036
references.citation: Eur J Neurosci. 2012 Nov;36(10):3356-64
references.pmid: 22882375
references.citation: Eur J Neurosci. 2003 Dec;18(12):3325-34
references.pmid: 14686905
references.citation: Brain Res Bull. 1999 Sep 1;50(1):33-9
references.pmid: 10507469
references.citation: Science. 1973 Nov 20;182(4115):939-41
references.pmid: 4745598
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10589-94
references.pmid: 18645186
references.citation: Neurosci Lett. 1995 Apr 28;190(1):41-4
references.pmid: 7624051
references.citation: Psychother Psychosom. 2002 May-Jun;71(3):141-50
references.pmid: 12021556
references.citation: Brain Res. 1984 Aug 13;308(2):387-91
references.pmid: 6383518
references.citation: Can J Urol. 1995 Dec;2(4):185-8
references.pmid: 12803708
references.citation: J Comp Neurol. 2000 Feb 21;417(4):399-414
references.pmid: 10701863
references.citation: J Pharmacol Exp Ther. 2012 May;341(2):518-31
references.pmid: 22357972
references.citation: Acta Paediatr. 2002;91(9):978-84; discussion 895-6
references.pmid: 12412876
references.citation: Psychopharmacology (Berl). 2005 Jul;180(2):215-23
references.pmid: 15696320
references.citation: Behav Brain Res. 2006 Dec 15;175(2):343-51
references.pmid: 17045347
references.citation: Neuroscience. 1999;91(4):1343-54
references.pmid: 10391441
references.citation: Psychopharmacology (Berl). 2012 Jul;222(2):325-36
references.pmid: 22322324
references.citation: Science. 1981 Sep 18;213(4514):1394-7
references.pmid: 6267699