title: Cathepsin S in the spinal microglia contributes to remifentanil-induced hyperalgesia in rats.
abstract: Cysteine protease Cathepsin S (CatS) expressed by spinal microglia has been shown to play a critical role in nerve injury and inflammation-induced chronic pain. However, whether microglial CatS contributes to remifentanil-induced acute hyperalgesia remains unstudied. In the present study, intravenous remifentanil infusion induced a significant increase in the expression of premature and mature form of CatS in the activated microglia in the spinal cord. Spinal delivery of irreversible CatS inhibitor LHVS reduced hyperalgesia, attenuated activation of spinal microglia and blocked phosphorylation of NMDA receptor NR1 subunit induced by remifentanil. Furthermore, inhibition of microglia by minocycline effectively suppressed remifentanil-induced hyperalgesia, as well as CatS upregulation. In addition, remifentanil infusion also induced an increase in reactive oxygen species (ROS) levels in spinal neurons. Systemic administration of ROS scavenger PBN was sufficient to suppress remifentanil-induced painful hypersensitivity. Removal of ROS by PBN prevented upregulation of mature CatS in spinal microglia. However, increased protein level of premature form of CatS was not affected by PBN. Altogether, our findings demonstrate that neuronal ROS promote maturation of microglial CatS which facilitates activation of NMDA in the spinal dorsal horn. Therefore, such mechanism is involved in neuron-microglia positive feedback and contributes to remifentanil-induced hyperalgesia.
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
authors.forename: L
authors.initials: L
authors.lastname: Ye
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
authors.forename: L
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China.
authors.forename: S Y
authors.initials: SY
authors.lastname: Yang
authors.affiliation: Neurobiology Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510000, China.
authors.forename: J J
authors.initials: JJ
authors.lastname: Duan
authors.affiliation: Neurobiology Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510000, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510000, China. Electronic address: cuiyu2@mail.sysu.edu.cn.
authors.forename: Y
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China. Electronic address: chen@mail.sysu.edu.cn.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D002403:Cathepsins / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008911:Minocycline / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000077208:Remifentanil; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014110:Touch; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000700:Analgesics; D016166:Free Radical Scavengers; C409466:NR1 NMDA receptor; D010880:Piperidines; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D002403:Cathepsins; C028217:cathepsin S; D008911:Minocycline; D000077208:Remifentanil
keywords: cathepsin S; hyperalgesia; microglia; minocycline; reactive oxygen species; remifentanil