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Recombinant human soluble thrombomodulin prevents peripheral HMGB 1‐dependent hyperalgesia in rats
Author(s) -
Tanaka Junichi,
Seki Yukari,
Ishikura Hiroyasu,
Tsubota Maho,
Sekiguchi Fumiko,
Yamaguchi Kaoru,
Murai Akira,
Umemura Takehiro,
Kawabata Atsufumi
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12396
Subject(s) - hyperalgesia , pharmacology , medicine , swelling , inflammation , dorsal root ganglion , sensitization , anesthesia , chemistry , nociception , immunology , dorsum , pathology , anatomy , receptor
Background and Purpose High‐mobility group box 1 ( HMGB 1), 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 HMGB 1 and promotes its degradation. Given evidence for involvement of HMGB 1 in pain signalling, we determined if peripheral HMGB 1 causes hyperalgesia, and then asked if rhsTM modulates the HMGB 1‐dependent hyperalgesia. Experimental Approach Mechanical nociceptive threshold and swelling in rat hindpaw were determined by the paw pressure test and by measuring paw thickness, respectively, and HMGB 1 levels in rat hindpaw plantar tissue, dorsal root ganglion ( DRG ) and serum were determined by W estern blotting or elisa . Key Results Intraplantar (i.pl.) administration of HMGB 1 rapidly evoked paw swelling and gradually caused hyperalgesia in rats. Systemic administration of rhsTM abolished HMGB 1‐induced hyperalgesia, and partially blocked paw swelling. LPS , administered i.pl., rapidly produced mild paw swelling, and gradually caused hyperalgesia. The anti‐ HMGB 1 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. HMGB 1 levels greatly decreased in the hindpaw, but not DRG . Serum HMGB 1 tended to increase after i.pl. LPS in rats pretreated with vehicle, but not rhsTM . Conclusion and Implications These data suggest that peripheral HMGB 1 causes hyperalgesia, and that rhsTM abolishes HMGB 1‐dependent hyperalgesia, providing novel evidence for therapeutic usefulness of rhsTM as an analgesic.