The thrombin-thrombomodulin (TM) complex generates activated forms of protein C (APC) and thrombin-activatable fibrinolysis inhibitor (TAFIa), known as carboxypeptidase B (CPB), and degrades high mobility group box 1 (HMGB1), a pronociceptive molecule. We have shown that soluble TM (TMα) prevents chemotherapy-induced peripheral neuropathy (CIPN) in rodents, and that APC and TAFIa/CPB, as well as HMGB1 degradation, contribute to the anti-CIPN effect of TMα. Given our recent evidence for the involvement of complement C5a, degradable by TAFIa/CPB, in CIPN, we analyzed the mechanisms for peripheral C5a-mediated pain in mice. Intraplantar (i.pl.) injection of C5a at 30-300 ng induced dose-dependent mechanical allodynia, as assessed by von Frey test, an effect abolished by i.p. administration of DF2593A, a mouse C5a receptor (C5aR) antagonist, TAFIa/CPB, TMα or an anti-HMGB1-neutralizing antibody. Systemic (i.p.), but not local (i.pl.), administration of liposomal clodronate, a macrophage depletor, partially reduced the C5a-induced allodynia. In macrophage-like RAW 264.7 cells, C5a caused HMGB1 release in the presence, but not absence, of a sub-effective concentration of lipopolysaccharide. Together, C5a-induced allodynia is considered to involve C5aR-dependent HMGB1 release from monocyte-derived macrophages and non-macrophage cells.