title: Spinal peroxynitrite contributes to remifentanil-induced postoperative hyperalgesia via enhancement of divalent metal transporter 1 without iron-responsive element-mediated iron accumulation in rats.
abstract: BACKGROUND
  Hyperalgesia is one of the negative consequences following intraoperative analgesia with remifentanil. Peroxynitrite is a critical determinant in nociceptive process. Peroxynitrite inactivates iron-sulfur cluster that results in mitochondrial dysfunction and the release of iron, leading to mitochondrial iron accumulation. Iron accumulation mediated by divalent metal transporter 1 (DMT1) plays a key role in N-methyl-D-aspartate neurotoxicity. This study aims to determine whether peroxynitrite contributes to remifentanil-induced postoperative hyperalgesia via DMT1-mediated iron accumulation.
  
  
  METHODS
  Behavior testing was performed in rat model at different time points. Three-nitrotyrosine, nitrated manganese superoxide dismutase, and DMT1 with/without iron-responsive element [DMT1(+)IRE and DMT1(-)IRE] in spinal cord were detected by Western blot and immunohistochemistry. Spinal iron concentration was measured using the Perl stain and atomic absorption spectrophotometer. Hydrogen-rich saline imparting selectivity for peroxynitrite decomposition and iron chelator was applied in mechanistic study on the roles of peroxynitrite and iron, as well as the prevention of hyperalgesia.
  
  
  RESULTS
  Remifentanil induced thermal and mechanical hyperalgesia at postoperative 48 h. Compared with control, there were higher levels of 3-nitrotyrosine (mean ± SD, hyperalgesia vs. control, 1.22 ± 0.18 vs. 0.25 ± 0.05, n = 4), nitrated manganese superoxide dismutase (1.01 ± 0.1 vs. 0.19 ± 0.03, n = 4), DMT1(-)IRE (1.42 ± 0.19 vs. 0.33 ± 0.06, n = 4), and iron concentration (12.87 ± 1.14 vs. 5.26 ± 0.61 μg/g, n = 6) in remifentanil-induced postoperative hyperalgesia, while DMT1(+)IRE was unaffected. Eliminating peroxynitrite with hydrogen-rich saline protected against hyperalgesia and attenuated DMT1(-)IRE overexpression and iron accumulation. Iron chelator prevented hyperalgesia in a dose-dependent manner.
  
  
  CONCLUSIONS
  Our study identifies that spinal peroxynitrite activates DMT1(-)IRE, leading to abnormal iron accumulation in remifentanil-induced postoperative hyperalgesia, while providing the rationale for the development of molecular hydrogen and "iron-targeted" therapies.
authors.affiliation: From the Department of Anesthesiology, Tianjin Medical University General Hospital, and Tianjin Research Institute of Anesthesiology, Tianjin, China.
authors.forename: Rui-Chen
authors.initials: RC
authors.lastname: Shu
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Zhang
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Wang
authors.forename: Ke-Liang
authors.initials: KL
authors.lastname: Xie
authors.forename: Yong-Hao
authors.initials: YH
authors.lastname: Yu
authors.forename: Guo-Lin
authors.initials: GL
authors.lastname: Wang
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000096:biosynthesis*; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D035925:Iron-Regulatory Proteins / Q000096:biosynthesis*; D008297:Male; D010149:Postoperative Pain / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000096:biosynthesis*; D010880:Piperidines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077208:Remifentanil; D013116:Spinal Cord / Q000378:metabolism*; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D007501:Iron; D035925:Iron-Regulatory Proteins; D030421:Peroxynitrous Acid; D010880:Piperidines; D000077208:Remifentanil; D000099236:Solute Carrier Family 11, Member 2