Role of Thrombin in Soluble Thrombomodulin-Induced Suppression of Peripheral HMGB1-Mediated Allodynia in Mice

High mobility group box 1 (hmgb1), a nuclear protein, once released into the extracellular space under pathological conditions, plays a pronociceptive role in redox-dependent distinct active forms, all-thiol hmgb1 (at-hmgb1) and disulfide hmgb1 (ds-hmgb1), that accelerate nociception through the receptor for advanced glycation endproducts (rage) and toll-like receptor 4 (tlr4), respectively. thrombomodulin (tm), an endothelial membrane protein, and soluble tm, known as tmα, promote thrombin-mediated activation of protein c and also sequester hmgb1, which might facilitate thrombin degradation of hmgb1. the present study aimed at clarifying the role of thrombin in tmα-induced suppression of peripheral hmgb1-dependent allodynia in mice. thrombin-induced degradation of at-hmgb1 and ds-hmgb1 was accelerated by tmα in vitro. intraplantar (i.pl.) injection of bovine thymus-derived hmgb1 in an unknown redox state, at-hmgb1, ds-hmgb1 or lipopolysaccharide (lps), known to cause hmgb1 secretion, produced long-lasting mechanical allodynia in mice, as assessed by von frey test. tmα, when preadministered i.pl., prevented the allodynia caused by bovine thymus-derived hmgb1, at-hmgb1, ds-hmgb1 or lps, in a dose-dependent manner. the tmα-induced suppression of the allodynia following i.pl. at-hmgb1, ds-hmgb1 or lps was abolished by systemic preadministration of argatroban, a thrombin-inhibiting agent, and accelerated by i.pl. co-administered thrombin. our data clearly indicate that tmα is capable of promoting the thrombin-induced degradation of both at-hmgb1 and ds-hmgb1, and suppresses the allodynia caused by either hmgb1 in a thrombin-dependent manner. considering the emerging role of hmgb1 in distinct pathological pain models, the present study suggests the therapeutic usefulness of tmα for treatment of intractable and/or persistent pain.