title: Role of the potassium chloride cotransporter isoform 2-mediated spinal chloride homeostasis in a rat model of visceral hypersensitivity.
abstract: Visceral hypersensitivity represents an important hallmark in the pathophysiology of irritable bowel syndrome (IBS), of which the mechanisms remain elusive. The present study was designed to examine whether cation-chloride cotransporter (CCC)-mediated chloride (Cl(-)) homeostasis of the spinal cord is involved in chronic stress-induced visceral hypersensitivity. Chronic visceral hypersensitivity was induced by exposing male Wistar rats to water avoidance stress (WAS). RT-PCR, Western blotting, and immunohistochemistry were used to assess the expression of CCCs in the spinal cord. Patch-clamp recordings were performed on adult spinal cord slices to evaluate Cl(-) homeostasis and Cl(-) extrusion capacity of lamina I neurons. Visceral sensitivity was estimated by measuring the abdominal withdrawal reflex in response to colorectal distension (CRD). After 10 days of WAS exposure, levels of both total protein and the oligomeric form of the K(+)-Cl(-) cotransporter isoform 2 (KCC2), but not Na(+)-K(+)-2Cl(-) transporter isoform 1 (NKCC1), were significantly decreased in the dorsal horn of the lumbosacral spinal cord. The downregulation of KCC2 resulted in a depolarizing shifted equilibrium potential of GABAergic inhibitory postsynaptic current and impaired Cl(-) extrusion capacity in lamina I neurons of the lumbosacral spinal cord from WAS rats. Acute noxious CRD disrupted spinal KCC2 expression and function 2 h after the final distention in sham rats, but not in WAS rats. Pharmacological blockade of KCC2 activity by intrathecal injection of a KCC2 inhibitor [(dihydroindenyl)oxy] alkanoic acid enhanced visceral nociceptive sensitivity in sham rats, but not in WAS rats. These results suggest that KCC2 downregulation-mediated impairment of spinal cord Cl(-) homeostasis may play an important role in chronic stress-induced visceral hypersensitivity.
authors: Department of Gastroenterology, Ruijin Hospital, Shanghai, China; and.
authors: Dong
authors: D
authors: Tang
authors: Department of Gastroenterology, Ruijin Hospital, Shanghai, China; and.
authors: Ai-Hua
authors: AH
authors: Qian
authors: Department of Gastroenterology, Ruijin Hospital, Shanghai, China; and.
authors: Dan-Dan
authors: DD
authors: Song
authors: Department of Gastroenterology, Ruijin Hospital, Shanghai, China; and.
authors: Qi-Wen
authors: QW
authors: Ben
authors: Department of Gastroenterology, Ruijin Hospital, Shanghai, China; and.
authors: Wei-Yan
authors: WY
authors: Yao
authors: Department of Gastroenterology, Ruijin Hospital, Shanghai, China; and.
authors: Jing
authors: J
authors: Sun
authors: Department of Anatomy, Histology and Embryology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Wei-Guang
authors: WG
authors: Li
authors: Department of Anatomy, Histology and Embryology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Tian-Le
authors: TL
authors: Xu
authors: Department of Gastroenterology, Ruijin Hospital, Shanghai, China; and yyz28@medmail.com.cn.
authors: Yao-Zong
authors: YZ
authors: Yuan
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002264:Carboxylic Acids / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis; D006930:Hyperalgesia / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007192:Indenes / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D040542:Mechanotransduction, Cellular; D059225:Nociception / Q000187:drug effects; D011312:Pressure; D017208:Rats, Wistar; D012018:Reflex; D013131:Spine / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013315:Stress, Psychological / Q000150:complications; D027981:Symporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D059265:Visceral Pain / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D002264:Carboxylic Acids; D002712:Chlorides; D007192:Indenes; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C059990:((dihydroindenyl)oxy)alkanoic acid
keywords: KCC2; irritable bowel syndrome; stress; visceral hypersensitivity