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

Ting, E., Guerrero, A. T. G., Cunha, T. M., Verri, W. A., Taylor, S. M., Woodruff, T. M., Cunha, F. Q. and Ferreira, S. H. (2008) Role of complement C5a in mechanical inflammatory hypernociception: potential use of C5a receptor antagonists to control inflammatory pain. British Journal of Pharmacology, 153 5: 1043-1053. doi:10.1038/sj.bjp.0707640


Author Ting, E.
Guerrero, A. T. G.
Cunha, T. M.
Verri, W. A.
Taylor, S. M.
Woodruff, T. M.
Cunha, F. Q.
Ferreira, S. H.
Title Role of complement C5a in mechanical inflammatory hypernociception: potential use of C5a receptor antagonists to control inflammatory pain
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
1476-5381
Publication date 2008-03-01
Year available 2008
Sub-type Article (original research)
DOI 10.1038/sj.bjp.0707640
Volume 153
Issue 5
Start page 1043
End page 1053
Total pages 10
Editor H. Rang
Place of publication London, United Kingdom
Publisher Macmillan
Language eng
Subject C1
320599 Pharmacology not elsewhere classified
730102 Immune system and allergy
110707 Innate Immunity
Formatted abstract
Abstract:
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 μg 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 E2 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 neutrophil-depleted 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.
Keyword Inflammatory pain
Hyperalgesia
C5a
Complement system
Neutrophils
Cytokines
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
School of Biomedical Sciences Publications
 
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Created: Thu, 01 May 2008, 09:02:31 EST by Timothy Hazelton on behalf of School of Biomedical Sciences