title: Glucocorticoid mediates water avoidance stress-sensitized colon-bladder cross-talk via RSK2/PSD-95/NR2B in rats.
abstract: Unexpected environmental and social stimuli could trigger stress. Although coping with stress is essential for survival, long-term stress impacts visceral functions, and therefore, it plays a role in the development and exacerbation of symptoms of gastrointestinal/urogenital disorders. The aim of this study is to characterize the role of corticosterone in stress-sensitized colon-bladder cross-talk, a phenomenon presumed to underlie the comorbidity of functional bowel and bladder disorders. Cystometry and protein/mRNA expression in the lumbosacral dorsal horn (L6-S1) in response to intracolonic mustard oil (MO) instillation were analyzed in female Wistar-Kyoto rats subjected to water avoidance stress (WAS; 1 h/day for 10 days) or sham stress (WAsham). Whereas it had no effect on baseline-voiding function, chronic stress upregulated plasma corticosterone concentration and dorsal horn spinal p90 ribosomal S6 kinase 2 (RSK2) protein/mRNA levels, and RSK2 immunoreactivity colocalized with NeuN-positive neurons. Intracolonic MO dose-dependently decreased intrercontraction intervals and threshold pressure, provoked spinal RSK2 and NR2B phosphorylation, and enhanced PSD-95-RSK2 and PSD-95-NR2B coupling. Intrathecal kaempferol (a RSK2 activation antagonist; 30 min before MO instillation), bilateral adrenalectomy (7 days prior the stress paradigm), and subcutaneous RU-38486 (a glucocorticoid receptor antagonist; 30 min daily before stress sessions), but not RU-28318 (a mineralocorticoid receptor antagonist), attenuated MO-induced bladder hyperactivity, protein phosphorylation, and protein-protein interactions in the WAS group. Our results suggest that stress-associated glucocorticoid release mediates WAS-dependent sensitization of colon-bladder cross-talk via the spinal RSK2/PSD-95/NR2B cascade and offer a possibility for developing pharmacological strategies for the treatment of stress-related pelvic pain.
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Hsien-Yu
authors.initials: HY
authors.lastname: Peng
authors.forename: Ming-Chun
authors.initials: MC
authors.lastname: Hsieh
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Lai
authors.forename: Gin-Den
authors.initials: GD
authors.lastname: Chen
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Huang
authors.forename: Tzer-Bin
authors.initials: TB
authors.lastname: Lin
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000097:blood*; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D005767:Gastrointestinal Diseases / Q000209:etiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D011921:Rats, Inbred WKY; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013315:Stress, Psychological / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D001745:Urinary Bladder Diseases / Q000209:etiology
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D006727:Hormone Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D011965:Receptors, Glucocorticoid; D016194:Receptors, N-Methyl-D-Aspartate; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D003345:Corticosterone