Role of complement C5a in mechanical inflammatory hypernociception: potential use of C5a receptor antagonists to control inflammatory pain

Abstract

Background and purpose: C5a, a complement activation product, exhibits a broad spectrum of inflammatory activities particularly neutrophil chemoattraction. Herein, the role of C5a in the genesis of inflammatory hypernociception was investigated in rats and mice using the specific C5a receptor antagonist PMX53 (AcF-[OP(D-Cha)WR]). Experimental approach: Mechanical hypernociception was evaluated with a modification of the Randall-Selitto test in rats and electronic pressure meter paw test in mice. Cytokines were measured by ELISA and neutrophil migration was determined by myeloperoxidase activity. Key results: Local pretreatment of rats with PMX53 (60-180 mg per paw) inhibited zymosan-, carrageenan-, lipopolysaccharide (LPS)-and antigen-induced hypernociception. These effects were associated with C5a receptor blockade since PMX53 also inhibited the hypernociception induced by zymosan-activated serum and C5a but not by the direct-acting hypernociceptive mediators, prostaglandin E 2 and dopamine. Underlying the C5a hypernociceptive mechanisms, PMX53 did not alter the cytokine release induced by inflammatory stimuli. However, PMX53 inhibited cytokine-induced hypernociception. PMX53 also inhibited the recruitment of neutrophils induced by zymosan but not by carrageenan or LPS, indicating an involvement of neutrophils in the hypernociceptive effect of C5a. Furthermore, the C5a-induced hypernociception was reduced in neutrophildepleted rats. Extending these findings in rats, blocking C5a receptors also reduced zymosan-induced joint hypernociception in mice. Conclusions and implications: These results suggest that C5a is an important inflammatory hypernociceptive mediator, acting by a mechanism independent of hypernociceptive cytokine release, but dependent on the presence of neutrophils. Therefore, we suggest that inhibiting the action of C5a has therapeutic potential in the control of inflammatory pain.

Selective and non‐selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna

“…PMX53 does reduce inflammatory hypernociception, however, and therefore has the potential to relieve inflammatory pain. 21 These data suggest the hypothesis that a c5a antagonist could provide necessary analgesia during (stress) fracture healing, without compromising the remodeling processes of bone healing.…”

“…20 It is a potent inflammatory mediator and is involved in the progression of immuno-inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease, asthma, and psoriasis. 21 A C5a receptor antagonist, PMX53, has been trialled as a NSAID, demonstrating potent inhibition of C5a mediated neutrophil chemotaxis, phagocytosis and leukocyte release of inflammatory cytokines. 22,23 Is has been used to target the complement system and has shown positive therapeutic effects in animal models of inflammatory arthritis.…”

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

“…Emerging evidences suggest that C5a, the anaphylatoxin produced by complement activation, has potent nociceptive activity in several models of inflammatory and neuropathic pain by interacting with its selective receptor C5aR (7,8). C5aR belongs to the class A subfamily of the seven-transmembrane (TM) G protein-coupled receptors (GPCR) (9) and is widely expressed in immune cells, including neutrophils (polymorphonuclear cells, PMN), monocytes, microglia, and in nonimmune cells, including neurons in the CNS and dorsal root ganglia (10,11).…”

Tephrosia sinapouethyl acetate extract inhibits inflammatory pain in mice: Opioid receptor dependent inhibition of TNFαand IL-1βproduction

“…In animals, LTB 4 -induced hyperalgesia was inhibited by leukocyte depletion (Levine et al, 1984). Recently, it has been demonstrated that neutrophils are important for the hyperalgesia induced by carrageenin, zymosan and antigen-induced inflammation by further producing nociceptive mediators including LTB 4 and PGE 2 (Cunha et al, 2008b;Guerrero et al, 2008;Ting et al, 2008;Verri et al, 2009). On the other hand, it has also been described that neutrophils can reduce hyperalgesia by releasing opioids at the local inflammatory site (Cunha & Verri, 2006;Rittner et al, 2006).…”