Activation of the complement system by injury increases inflammation by producing complement fragments C5a and C3a which are able to recruit and activate immune cells. Complement activation may contribute to pain after inflammation and injury. In this study, we examined whether C5a and C3a elicit nociception when injected into mouse hind paws in vivo, and whether C5a and C3a activate and/or sensitize mechanosensitive nociceptors when applied on peripheral terminals in vitro. We also examined the dorsal root ganglia (DRG) for C5a receptor (C5aR) mRNA and effects of C5a and C3a on intracellular Ca(2+) concentration ([Ca(2+)](i)) using Ca(2+) imaging. Heat hyperalgesia was elicited by intraplantar injection of C5a, and mechanical hyperalgesia by C5a and C3a. After exposure to either C5a or C3a, C-nociceptors were sensitized to heat as evidenced by an increased proportion of heat responsive fibers, lowered response threshold to heat and increased action potentials during and after heat stimulation. A-nociceptors were activated by complement. However, no change was observed in mechanical responses of A- and C-nociceptors after C5a and C3a application. The presence of C5aR mRNA was detected in DRG. C5a and C3a application elevated [Ca(2+)](i) and facilitated capsaicin-induced [Ca(2+)](i) responses in DRG neurons. The results suggest a potential role for complement fragments C5a and C3a in nociception by activating and sensitizing cutaneous nociceptors.