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      Adrenergic β 2-Receptors Mediates Visceral Hypersensitivity Induced by Heterotypic Intermittent Stress in Rats

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          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 β 2-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 β 2 adrenoceptor antagonist but not by β 1- or β 3-adrenoceptor antagonist. Administration of a selective β 2-adrenoceptor antagonist also normalized hyperexcitability of colon-innervating DRG neurons of HIS rats. Furthermore, administration of β-adrenoceptor antagonist suppressed sustained potassium current density ( I K) without any alteration of fast-inactivating potassium current density ( I A). Conversely, administration of NE enhanced the neuronal excitability and produced visceral hypersensitivity in healthy control rats, and blocked by β 2-adrenoceptor antagonists. In addition, HIS significantly enhanced the NE concentration in the blood plasma but did not change the expression of β 2-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.

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          Most cited references33

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          A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development.

          The irritable bowel syndrome (IBS) is a common disorder characterized by abdominal pain in the setting of altered perception of viscerosensory stimuli. This so-called visceral hyperalgesia occurs in the absence of detectable organic disease in the peripheral organs and may cause normal or physiologic contractions to be perceived as painful. Although the pathogenesis of IBS remains speculative and is probably multifactorial, a prevailing paradigm is that transient noxious events lead to long-lasting sensitization of the neural pain circuit, despite complete resolution of the initiating event. Neonatal male Sprague-Dawley rats received either mechanical or chemical colonic irritation between postnatal days 8 and 21 and were tested when they became adults. The abdominal withdrawal reflex and the responses of viscerosensitive neurons were recorded during colon distention. Colon irritation in neonates, but not in adults, results in chronic visceral hypersensitivity, with characteristics of allodynia and hyperalgesia, associated with central neuronal sensitization in the absence of identifiable peripheral pathology. These results concur largely with observations in patients with IBS, providing a new animal model to study IBS and validating a neurogenic component of functional abdominal pain that encourages novel approaches to health care and research.
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            Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin.

            The adenylate cyclase system, which consists of a catalytic moiety and regulatory guanine nucleotide-binding proteins, provides the effector mechanism for the intracellular actions of many hormones and drugs. The tissue specificity of the system is determined by the particular receptors that a cell expresses. Of the many receptors known to modulate adenylate cyclase activity, the best characterized and one of the most pharmacologically important is the beta-adrenergic receptor (beta AR). The pharmacologically distinguishable subtypes of the beta-adrenergic receptor, beta 1 and beta 2 receptors, stimulate adenylate cyclase on binding specific catecholamines. Recently, the avian erythrocyte beta 1, the amphibian erythrocyte beta 2 and the mammalian lung beta 2 receptors have been purified to homogeneity and demonstrated to retain binding activity in detergent-solubilized form. Moreover, the beta-adrenergic receptor has been reconstituted with the other components of the adenylate cyclase system in vitro, thus making this hormone receptor particularly attractive for studies of the mechanism of receptor action. This situation is in contrast to that for the receptors for growth factors and insulin, where the primary biochemical effectors of receptor action are unknown. Here, we report the cloning of the gene and cDNA for the mammalian beta 2AR. Analysis of the amino-acid sequence predicted for the beta AR indicates significant amino-acid homology with bovine rhodopsin and suggests that, like rhodopsin, beta AR possesses multiple membrane-spanning regions.
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              Distinct potassium channels on pain-sensing neurons.

              Differential expression of ion channels contributes functional diversity to sensory neuron signaling. We find nerve injury induced by the Chung model of neuropathic pain leads to striking reductions in voltage-gated K(+) (Kv) channel subunit expression in dorsal root ganglia (DRG) neurons, suggesting a potential molecular mechanism for hyperexcitability of injured nerves. Moreover, specific classes of DRG neurons express distinct Kv channel subunit combinations. Importantly, Kv1.4 is the sole Kv1 alpha subunit expressed in smaller diameter neurons, suggesting that homomeric Kv1.4 channels predominate in A delta and C fibers arising from these cells. These neurons are presumably nociceptors, because they also express the VR-1 capsaicin receptor, calcitonin gene-related peptide, and/or Na(+) channel SNS/PN3/Nav1.8. In contrast, larger diameter neurons associated with mechanoreception and proprioception express high levels of Kv1.1 and Kv1.2 without Kv1.4 or other Kv1 alpha subunits, suggesting that heteromers of these subunits predominate on large, myelinated afferent axons that extend from these cells.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                14 April 2014
                : 9
                : 4
                : e94726
                Affiliations
                [1 ]Department of Gastroenterology, the Second Affiliated Hospital, Soochow University, Suzhou, P. R. China
                [2 ]Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China
                Zhejiang University School of Medicine, China
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GYX. Performed the experiments: CZ YYR YYZ ZJ. Analyzed the data: HZ CYH YX. Contributed reagents/materials/analysis tools: GYX. Wrote the paper: GYX YX HZ CYH.

                Article
                PONE-D-14-02041
                10.1371/journal.pone.0094726
                3986230
                24733123
                b6fd41d8-0c37-4fad-9c80-592db2fa394d
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 14 January 2014
                : 18 March 2014
                Page count
                Pages: 13
                Funding
                This work was supported by grants from National Natural Science Foundation of China (81070884, 81230024 and 31300909) and from Jiangsu Distinguished Professor Program of Jiangsu Province (SR21500111) and the Priority Academic Program Development of Jiangsu Higher Education Institutions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Neuroscience
                Cognitive Neuroscience
                Medicine and Health Sciences
                Pain Management
                Pain

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                Uncategorized

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