title: Long-term upregulation of cortical glutamatergic AMPA receptors in a mouse model of chronic visceral pain.
abstract: BACKGROUND
  Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders and it causes long-lasting visceral pain and discomfort. AMPA receptor mediated long-term potentiation (LTP) has been shown to play a critical role in animal models of neuropathic and inflammatory pain. No report is available for central changes in the ACC of mice with chronic visceral pain.
  
  
  RESULTS
  In this study, we used integrative methods to investigate potential central plastic changes in the anterior cingulate cortex (ACC) of a visceral pain mouse model induced by intracolonic injection of zymosan. We found that visceral pain induced an increased expression of AMPA receptors (at the post synapses) in the ACC via an enhanced trafficking of the AMPA receptors to the membrane. Both GluA1 and GluA2/3 subunits were significantly increased. Supporting biochemical changes, excitatory synaptic transmission in the ACC were also significantly enhanced. Microinjection of AMPA receptor inhibitor IEM1460 into the ACC inhibited visceral and spontaneous pain behaviors. Furthermore, we found that the phosphorylation of GluA1 at the Ser845 site was increased, suggesting that GluA1 phosphorylation may contribute to AMPA receptor trafficking. Using genetically knockout mice lacking calcium-calmodulin stimulated adenylyl cyclase subtype 1 (AC1), we found that AMPA receptor phosphorylation and its membrane trafficking induced by zymosan injection were completely blocked.
  
  
  CONCLUSIONS
  Our results provide direct evidence for cortical AMPA receptors to contribute to zymosan-induced visceral and spontaneous pain and inhibition of AC1 activity may help to reduce chronic visceral pain.
authors.affiliation: Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, 28 Xianning West Road, Xian, Shaanxi, 710049, China. liushb1974@aliyun.com.|Department of Pharmacology, Pharmacy of School, Fourth Military Medical University, Xian, Shaanxi, 710032, China. liushb1974@aliyun.com.|Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. liushb1974@aliyun.com.
authors.forename: Shui-Bing
authors.initials: SB
authors.lastname: Liu
authors.affiliation: Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, 28 Xianning West Road, Xian, Shaanxi, 710049, China. mmzhang@fmmu.edu.cn.|Department of Pharmacology, Pharmacy of School, Fourth Military Medical University, Xian, Shaanxi, 710032, China. mmzhang@fmmu.edu.cn.|Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. mmzhang@fmmu.edu.cn.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Fourth Military Medical University, Xian, Shaanxi, 710032, China. chenglfz@fmmu.edu.cn.
authors.forename: Lin-Feng
authors.initials: LF
authors.lastname: Cheng
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. barbarashi8@gmail.com.
authors.forename: Jiao
authors.initials: J
authors.lastname: Shi
authors.affiliation: Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, 28 Xianning West Road, Xian, Shaanxi, 710049, China. lujs33@163.com.
authors.forename: Jing-Shan
authors.initials: JS
authors.lastname: Lu
authors.affiliation: Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi'an Jiaotong University, 28 Xianning West Road, Xian, Shaanxi, 710049, China. min.zhuo@utoronto.ca.|Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. min.zhuo@utoronto.ca.
authors.forename: Min
authors.initials: M
authors.lastname: Zhuo
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D059350:Chronic Pain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D017353:Gene Deletion; D005971:Glutamates / Q000378:metabolism*; D006179:Gyrus Cinguli / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007267:Injections; D043183:Irritable Bowel Syndrome / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D018091:Receptors, AMPA / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D059265:Visceral Pain / Q000378:metabolism* / Q000473:pathology; D015054:Zymosan
chemical_list: D005971:Glutamates; C110702:IEM 1460; D018091:Receptors, AMPA; D010768:Phosphoserine; D015054:Zymosan; D000262:Adenylyl Cyclases; D000218:Adamantane; D002118:Calcium