title: Neonatal colonic inflammation sensitizes voltage-gated Na(+) channels via upregulation of cystathionine β-synthetase expression in rat primary sensory neurons.
abstract: The pathogenesis of pain in irritable bowel syndrome (IBS) is poorly understood, and treatment remains difficult. We have previously reported that colon-specific dorsal root ganglion (DRG) neurons were hyperactive in a rat model of IBS induced by neonatal colonic inflammation (NCI). This study was designed to examine plasticity of voltage-gated Na(+) channel activities and roles for the endogenous hydrogen sulfide-producing enzyme cystathionine β-synthetase (CBS) in chronic visceral hyperalgesia. Abdominal withdrawal reflex (AWR) scores were recorded in response to graded colorectal distention in adult male rats as a measure of visceral hypersensitivity. Colon-specific DRG neurons were labeled with 1,1'-dioleyl-3,3,3',3-tetramethylindocarbocyanine methanesulfonate and acutely dissociated for measuring Na(+) channel currents. Western blot analysis was employed to detect changes in expressions of voltage-gated Na(+) (Na(V)) channel subtype 1.7, Na(V)1.8, and CBS. NCI significantly increased AWR scores when compared with age-matched controls. NCI also led to an ~2.5-fold increase in Na(+) current density in colon-specific DRG neurons. Furthermore, NCI dramatically enhanced expression of Na(V)1.7, Na(V)1.8, and CBS in colon-related DRGs. CBS was colocalized with Na(V)1.7 or -1.8 in colon-specific DRG neurons. Administration of O-(carboxymethyl)hydroxylamine hemihydrochloride (AOAA), an inhibitor for CBS, remarkably suppressed Na(+) current density and reduced expression of Na(V)1.7 and Na(V)1.8. More importantly, intraperitoneal or intrathecal application of AOAA attenuated AWR scores in NCI rats in a dose-dependent manner. These data suggest that NCI enhances Na(+) channel activity of colon DRG neurons, which is most likely mediated by upregulation of CBS expression, thus identifying a potential target for treatment for chronic visceral pain in patients with IBS.
authors: Institute of Neuroscience, Laboratory for Translational Pain Medicine, Department of Neurobiology, Soochow University, Suzhou, Peoples Republic of China.
authors: Ruobing
authors: R
authors: Qu
authors: Jingde
authors: J
authors: Tao
authors: Yongmeng
authors: Y
authors: Wang
authors: Youlang
authors: Y
authors: Zhou
authors: Geping
authors: G
authors: Wu
authors: Ying
authors: Y
authors: Xiao
authors: Chuang-Ying
authors: CY
authors: Hu
authors: Xinghong
authors: X
authors: Jiang
authors: Guang-Yin
authors: GY
authors: Xu
mesh_terms: D019342:Acetic Acid; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002232:Carbocyanines; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D004396:Coloring Agents; D003541:Cystathionine beta-Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005727:Ganglia, Spinal / Q000502:physiology*; D006930:Hyperalgesia / Q000503:physiopathology; D043183:Irritable Bowel Syndrome / Q000503:physiopathology; D008297:Male; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000096:biosynthesis / Q000502:physiology*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012020:Reflex, Abdominal / Q000187:drug effects
chemical_list: C582073:1,1'-dioleyl-3,3,3',3'-tetramethylindocarbocyanine; D002232:Carbocyanines; D004396:Coloring Agents; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568319:Scn10a protein, rat; C503480:Scn9a protein, rat; D000625:Aminooxyacetic Acid; D003541:Cystathionine beta-Synthase; D019342:Acetic Acid
keywords: dorsal root ganglion; hydrogen sulfide; irritable bowel syndrome; visceral pain