Nociceptive sensitization by complement C5a and C3a in mouse

Abstract

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 the present 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.

Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief

“…Recent evidence showed that C5aR is expressed in primary nociceptive neurons and that C5a could directly sensitize these fibers (12,13). Our studies showed that DF2593A blocked carrageenan and C5a-dependent mechanical hyperalgesia in vivo without sedative or central opioid-like effects.…”

“…For example, C5a was produced at the inflammatory sites and elicited mechanical hyperalgesia by activating the C5aR on infiltrated PMN (7). Direct intraplantar injection of C5a in mice elicited both heat and mechanical hyperalgesia by sensitizing primary afferent C-nociceptors (12,13). Local activation of C5aR has been also implicated in the pathogenesis of postsurgical pain, a model of postoperative pain (13).…”

Passive transfer autoimmunity in a mouse model of complex regional pain syndrome

“…Based on these experiments we postulated that fracture can induce the regional expression of novel antigens in the fracture limb hindpaw skin and sciatic nerve, subsequently triggering B cells to secret autoantibodies capable of binding to those antigens and initiating a regionally restricted antibody-antigen-complement response resulting in complement sensitization of nociceptive neurons [23]. The current study tested the hypothesis that serum antibodies from fracture mice can induce regionally restricted pain behaviors in B cell deficient fracture mice and proceeded to identify the immunoglobulin isotype responsible for these pronociceptive effects.…”

Inflammatory mediators involved in the paw edema and hyperalgesia induced by Batroxase, a metalloproteinase isolated from Bothrops atrox snake venom

“…The activation of nociceptors is achieved by substances that interact with receptors and/or ion channels, leading to changes on the excitability of primary and central sensorial neurons and the induction of nociception in response to a stimulus [78]. Inflammatory mediators such as cytokines and chemokines (TNF-α, IL-1 and IL-8) [20], bradykinin [29,74], complement factors C3a and C5a [40], prostaglandins [28] and leukotrienes [18], sympathomimetic amines [30], PAF, histamine and serotonin [11] are released at the site of inflammation and act on specific receptors and/or ion channels present in the peripheral terminals of nerve fibers, causing sensitization [17,77]. These mediators are released by inflammatory cells, including mast cells [3].…”