title: N-acetyl-cysteine attenuates remifentanil-induced postoperative hyperalgesia via inhibiting matrix metalloproteinase-9 in dorsal root ganglia.
abstract: Treatment of remifentanil-induced postoperative hyperalgesia (RIH) remains a clinical challenge because the mechanisms are not fully understood. Matrix metalloproteinase-9 (MMP-9) is a key component in neuroinflammation because of its facilitation of pro-inflammatory cytokine maturation. Therefore, inhibition of MMP-9 may represent a novel therapeutic approach to the treatment of RIH. Sprague-Dawley rats were randomly divided into three groups: Control, Incision and Remifentanil. A right plantar surgical incision was performed in Group Incision, and intraoperative remifentanil (0.04 mg/kg, 0.4 ml) was infused subcutaneously for 30 min in Group Remifentanil. The results indicated that intraoperative remifentanil induced an up-regulation and activation of MMP-9 in DRGs but not spinal cords. MMP-9 was expressed primarily in DRG neurons co-expressing mu opioid receptors (MOR), and elicited interleukin-1β (IL-1β) cleavage in DRG neurons and satellite glial cells (SGCs). Intraperitoneal injection of N-acetyl-cysteine (NAC), a broadly used safe drug, significantly attenuated RIH via suppressing the activation of MMP-9 in DRGs. NAC inhibited the cleavage of IL-1β in DRGs, which is a critical substrate of MMP-9, and markedly suppressed glial activation and neuron excitability in spinal dorsal horn induced by remifentanil. These results demonstrated that NAC can effectively alleviate RIH via powerfully inhibiting MMP-9 activation in DRGs.
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
authors.forename: Yu-E
authors.initials: YE
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
authors.forename: Zhengliang
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Gu
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control*; D055104:Infusions, Subcutaneous; D007274:Injections, Intraperitoneal; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010147:Pain Measurement / Q000379:methods; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000633:toxicity; D011184:Postoperative Period; D011493:Protein Kinase C / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000077208:Remifentanil
chemical_list: D000701:Analgesics, Opioid; D016166:Free Radical Scavengers; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C087857:protein kinase C gamma; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D000077208:Remifentanil; D000111:Acetylcysteine
keywords: N-acetyl-cysteine (NAC); dorsal root ganglia (DRG); matrix metalloproteinase-9 (MMP-9); remifentanil-induced hyperalgesia (RIH)