title: Recombinant human soluble thrombomodulin prevents peripheral HMGB1-dependent hyperalgesia in rats.
abstract: OBJECTIVE
  High-mobility group box 1 (HMGB1), a nuclear protein, is actively or passively released during inflammation. Recombinant human soluble thrombomodulin (rhsTM), a medicine for treatment of disseminated intravascular coagulation (DIC), sequesters HMGB1 and promotes its degradation. Given evidence for involvement of HMGB1 in pain signalling, we determined if peripheral HMGB1 causes hyperalgesia, and then asked if rhsTM modulates the HMGB1-dependent hyperalgesia.
  
  
  METHODS
  Mechanical nociceptive threshold and swelling in rat hindpaw were determined by the paw pressure test and by measuring paw thickness, respectively, and HMGB1 levels in rat hindpaw plantar tissue, dorsal root ganglion (DRG) and serum were determined by Western blotting or elisa.
  
  
  RESULTS
  Intraplantar (i.pl.) administration of HMGB1 rapidly evoked paw swelling and gradually caused hyperalgesia in rats. Systemic administration of rhsTM abolished HMGB1-induced hyperalgesia, and partially blocked paw swelling. LPS, administered i.pl., rapidly produced mild paw swelling, and gradually caused hyperalgesia. The anti-HMGB1 neutralizing antibody abolished LPS-induced hyperalgesia, but partially inhibited paw swelling. rhsTM at a high dose, 10 mg kg(-1) , prevented both hyperalgesia and paw swelling caused by LPS. In contrast, rhsTM at low doses, 0.001-1 mg kg(-1) , abolished the LPS-induced hyperalgesia, but not paw swelling. HMGB1 levels greatly decreased in the hindpaw, but not DRG. Serum HMGB1 tended to increase after i.pl. LPS in rats pretreated with vehicle, but not rhsTM.
  
  
  CONCLUSIONS
  These data suggest that peripheral HMGB1 causes hyperalgesia, and that rhsTM abolishes HMGB1-dependent hyperalgesia, providing novel evidence for therapeutic usefulness of rhsTM as an analgesic.
authors.affiliation: Division of Pharmacology & Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka, 577-8502, Japan; Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka, 814-0180, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Tanaka
authors.forename: Yukari
authors.initials: Y
authors.lastname: Seki
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ishikura
authors.forename: Maho
authors.initials: M
authors.lastname: Tsubota
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sekiguchi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Murai
authors.forename: Takehiro
authors.initials: T
authors.lastname: Umemura
authors.forename: Atsufumi
authors.initials: A
authors.lastname: Kawabata
mesh_terms: D000818:Animals; D005528:Foot / Q000473:pathology / Q000502:physiology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D024243:HMGB1 Protein / Q000097:blood / Q000502:physiology*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D018180:Thrombomodulin / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C546931:THBD protein, human; D018180:Thrombomodulin; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4
keywords: edema; high-mobility group box 1 (HMGB1); hyperalgesia; lipopolysaccharide; pain; thrombomodulin