title: Adrenergic β2-receptors mediates visceral hypersensitivity induced by heterotypic intermittent stress in rats.
abstract: Chronic visceral pain in patients with irritable bowel syndrome (IBS) has been difficult to treat effectively partially because its pathophysiology is not fully understood. Recent studies show that norepinephrine (NE) plays an important role in the development of visceral hypersensitivity. In this study, we designed to investigate the role of adrenergic signaling in visceral hypersensitivity induced by heterotypical intermittent stress (HIS). Abdominal withdrawal reflex scores (AWRs) used as visceral sensitivity were determined by measuring the visceromoter responses to colorectal distension. Colon-specific dorsal root ganglia neurons (DRGs) were labeled by injection of DiI into the colon wall and were acutely dissociated for whole-cell patch-clamp recordings. Blood plasma level of NE was measured using radioimmunoassay kits. The expression of β2-adrenoceptors was measured by western blotting. We showed that HIS-induced visceral hypersensitivity was attenuated by systemic administration of a β-adrenoceptor antagonist propranolol, in a dose-dependent manner, but not by a α-adrenoceptor antagonist phentolamine. Using specific β-adrenoceptor antagonists, HIS-induced visceral hypersensitivity was alleviated by β2 adrenoceptor antagonist but not by β1- or β3-adrenoceptor antagonist. Administration of a selective β2-adrenoceptor antagonist also normalized hyperexcitability of colon-innervating DRG neurons of HIS rats. Furthermore, administration of β-adrenoceptor antagonist suppressed sustained potassium current density (IK) without any alteration of fast-inactivating potassium current density (IA). Conversely, administration of NE enhanced the neuronal excitability and produced visceral hypersensitivity in healthy control rats, and blocked by β2-adrenoceptor antagonists. In addition, HIS significantly enhanced the NE concentration in the blood plasma but did not change the expression of β2-adrenoceptor in DRGs and the muscularis externa of the colon. The present study might provide a potential molecular target for therapy of visceral hypersensitivity in patents with IBS.
authors.affiliation: Department of Gastroenterology, the Second Affiliated Hospital, Soochow University, Suzhou, P. R. China; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China.
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: Rui
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ju
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China.
authors.forename: Hong-Hong
authors.initials: HH
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, the Second Affiliated Hospital, Soochow University, Suzhou, P. R. China.
authors.forename: Chuang-Ying
authors.initials: CY
authors.lastname: Hu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Gastroenterology, the Second Affiliated Hospital, Soochow University, Suzhou, P. R. China; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China.
authors.forename: Guang-Yin
authors.initials: GY
authors.lastname: Xu
mesh_terms: D000818:Animals; D002078:Butoxamine / Q000737:chemistry; D003106:Colon / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000378:metabolism; D043183:Irritable Bowel Syndrome / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D018408:Patch-Clamp Techniques; D010646:Phentolamine / Q000737:chemistry; D011433:Propranolol / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D059265:Visceral Pain / Q000378:metabolism*
chemical_list: D018343:Receptors, Adrenergic, beta-2; D002078:Butoxamine; D011433:Propranolol; D009638:Norepinephrine; D010646:Phentolamine
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