title: Neuron-restrictive silencer factor in periaqueductal gray contributes to remifentanil-induced postoperative hyperalgesia via repression of the mu-opioid receptor.
abstract: BACKGROUND
  The ultra-short-acting mu-opioid receptor (MOR) agonist remifentanil induces postoperative hyperalgesia both in preclinical and clinical research studies. However, the precise mechanisms remain unclear, although changes in opioid receptor expression might be a correlative feature. Neuron-restrictive silencer factor (NRSF) functions as a crucial regulator of MOR expression in specific neuronal cells. Using a mouse model of incisional postoperative pain, we assessed the expression of MOR and NRSF and investigated whether disruption of NRSF expression could prevent the postoperative nociceptive sensitization induced by surgical incision and subcutaneous infusion of remifentanil.
  
  
  METHODS
  Paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were independently used to assess mechanical allodynia and thermal hyperalgesia after surgery and cerebral ventricle injection of NRSF antisense oligonucleotide. Western blotting analyses were preformed to assess the expression levels of MOR and NRSF.
  
  
  RESULTS
  NRSF expression levels were enhanced after intraoperative infusion of remifentanil, resulting in repression of MOR expression in the periaqueductal gray (PAG). NRSF blockade with an NRSF antisense oligonucleotide significantly enhanced the expression levels of MOR and alleviated mechanical allodynia and thermal hyperalgesia induced by intraoperative infusion of remifentanil.
  
  
  CONCLUSIONS
  NRSF functions as a negative regulator of MOR in PAG and contributes to remifentanil-induced postoperative hyperalgesia. NRSF in PAG may be a potential target for this pain therapy.
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical College of Nanjing University, 321 Zhong Shan North Road, Nanjing 210008, Jiangsu Province, China. Electronic address: lucuie608@163.com.
authors.forename: Cui'e
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical College of Nanjing University, 321 Zhong Shan North Road, Nanjing 210008, Jiangsu Province, China. Electronic address: mengmeng19880914@163.com.
authors.forename: Linyu
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical College of Nanjing University, 321 Zhong Shan North Road, Nanjing 210008, Jiangsu Province, China. Electronic address: zhangjuanju@163.com.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing 210008, Jiangsu Province China. Electronic address: 778974454@qq.com.
authors.forename: Mingjian
authors.initials: M
authors.lastname: Kong
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical College of Nanjing University, 321 Zhong Shan North Road, Nanjing 210008, Jiangsu Province, China. Electronic address: liuyueseu@163.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical College of Nanjing University, 321 Zhong Shan North Road, Nanjing 210008, Jiangsu Province, China. Electronic address: zymzk608@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical College of Nanjing University, 321 Zhong Shan North Road, Nanjing 210008, Jiangsu Province, China. Electronic address: 13913846977@126.com.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing 210008, Jiangsu Province China. Electronic address: 1198364794@qq.com.
authors.forename: Jianhua
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical College of Nanjing University, 321 Zhong Shan North Road, Nanjing 210008, Jiangsu Province, China. Electronic address: mazhengliang1964@nju.edu.cn.
authors.forename: Zhengliang
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical College of Nanjing University, 321 Zhong Shan North Road, Nanjing 210008, Jiangsu Province, China. Electronic address: 13813996903@126.com.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Gu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism*; D010880:Piperidines / Q000633:toxicity; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D000077208:Remifentanil; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016896:Treatment Outcome; D000099229:RE1-Silencing Transcription Factor
chemical_list: D016376:Oligonucleotides, Antisense; D010880:Piperidines; D017450:Receptors, Opioid, mu; D000077208:Remifentanil; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor
keywords: Neuron-restrictive silencer factor; Periaqueductal gray; Postoperative hyperalgesia; Remifentanil; mu-Opioid receptor