title: Sensitization of neurons in the central nucleus of the amygdala via the decreased GABAergic inhibition contributes to the development of neuropathic pain-related anxiety-like behaviors in rats.
abstract: BACKGROUND
  Despite high prevalence of anxiety accompanying with chronic pain, the mechanisms underlying pain-related anxiety are largely unknown. With its well-documented role in pain and emotion processing, the amygdala may act as a key player in pathogenesis of neuropathic pain-related anxiety. Pain-related plasticity and sensitization of CeA (central nucleus of the amygdala) neurons have been shown in several models of chronic pain. In addition, firing pattern of neurons with spike output can powerfully affect functional output of the brain nucleus, and GABAergic neurons are crucial in the modulation of neuronal excitability. In this study, we first investigated whether pain-related plasticity (e.g. alteration of neuronal firing patterns) and sensitization of CeA neurons contribute to nerve injury-evoked anxiety in neuropathic rats. Furthermore, we explored whether GABAergic disinhibition is responsible for regulating firing patterns and intrinsic excitabilities of CeA neurons as well as for pain-related anxiety in neuropathic rats.
  
  
  RESULTS
  We discovered that spinal nerve ligation (SNL) produced neuropathic pain-related anxiety-like behaviors in rats, which could be specifically inhibited by intra-CeA administration of anti-anxiety drug diazepam. Moreover, we found potentiated plasticity and sensitization of CeA neurons in SNL-induced anxiety rats, of which including: 1) increased burst firing pattern and early-adapting firing pattern; 2) increased spike frequency and intrinsic excitability; 3) increased amplitude of both after-depolarized-potential (ADP) and sub-threshold membrane potential oscillation. In addition, we observed a remarkable reduction of GABAergic inhibition in CeA neurons in SNL-induced anxiety rats, which was proved to be important for altered firing patterns and hyperexcitability of CeA neurons, thereby greatly contributing to the development of neuropathic pain-related anxiety. Accordantly, activation of GABAergic inhibition by intra-CeA administration of muscimol, a selective GABAA receptors agonist, could inhibit SNL-induced anxiety-like behaviors in neuropathic rats. By contrast, suppression of GABAergic inhibition by intra-CeA administration of bicuculline, a selective GABAA receptors antagonist, produced anxiety-like behavior in normal rats.
  
  
  CONCLUSIONS
  This study suggests that reduction of GABAergic inhibition may be responsible for potentiated plasticity and sensitization of CeA neurons, which likely underlie the enhanced output of amygdala and neuropathic pain-related anxiety in SNL rats.
authors.affiliation: Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Beijing, 100191, P.R. China. jianghongzd@sina.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Beijing, 100191, P.R. China. fangdong@163.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Fang
authors.affiliation: Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Beijing, 100191, P.R. China. cristina88china@163.com.
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Kong
authors.affiliation: Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Beijing, 100191, P.R. China. 18704032913@163.com.
authors.forename: Zi-Run
authors.initials: ZR
authors.lastname: Jin
authors.affiliation: Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Beijing, 100191, P.R. China. 15810017232@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.affiliation: Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Beijing, 100191, P.R. China. kangxuejing@126.com.
authors.forename: Xue-Jing
authors.initials: XJ
authors.lastname: Kang
authors.affiliation: Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, P.R. China. ywan@hsc.pku.edu.cn.|Key Laboratory for Neuroscience, Ministry of Education and Ministry of Health, Beijing, 100191, P.R. China. ywan@hsc.pku.edu.cn.
authors.forename: You
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Neuroscience Research Institute, Peking University, 38 Xue-Yuan Road, Beijing, 100191, P.R. China. ggxing@bjmu.edu.cn.|Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, P.R. China. ggxing@bjmu.edu.cn.|Key Laboratory for Neuroscience, Ministry of Education and Ministry of Health, Beijing, 100191, P.R. China. ggxing@bjmu.edu.cn.
authors.forename: Guo-Gang
authors.initials: GG
authors.lastname: Xing
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001007:Anxiety / Q000150:complications / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal; D001640:Bicuculline / Q000494:pharmacology; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D066274:Central Amygdaloid Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006930:Hyperalgesia / Q000150:complications / Q000473:pathology; D020287:In Situ Nick-End Labeling; D008026:Ligation; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects; D009437:Neuralgia / Q000150:complications / Q000473:pathology*; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000473:pathology
chemical_list: D009118:Muscimol; D053148:Caspase 3; D001640:Bicuculline