Research Paper
Subject Category: Immunopharmacology and inflammation
British Journal of Pharmacology (2008) 154, 460–470; doi:10.1038/bjp.2008.94; published online 24 March 2008
Treatment with DF 2162, a non-competitive allosteric inhibitor of CXCR1/2, diminishes neutrophil influx and inflammatory hypernociception in mice
T M Cunha1, M M Barsante2, A T Guerrero1, W A Verri Jr1, S H Ferreira1, F M Coelho2, R Bertini3, C Di Giacinto3, M Allegretti3, F Q Cunha1 and M M Teixeira2
- 1Department of Pharmacology, Faculty of Medicine of Ribeirão Preto University of Sao Paulo, Ribeirão Preto, Sao Paulo, Brazil
- 2Departamento de Bioquímica e Imunologia, Instituto Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- 3Department of Preclinical Pharmacology, Dompé pha.r.ma s.p.a., L'Aquila, Italy
Correspondence: Dr MM Teixeira, Departamento de Bioquímica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627—Pampulha, Belo Horizonte, MG 31270-901, Brasil. E-mail: mmtex@icb.ufmg.br
Received 4 December 2007; Revised 30 January 2008; Accepted 19 February 2008; Published online 24 March 2008.
Abstract
Background and purpose:
Neutrophil migration into tissues is involved in the genesis of inflammatory pain. Here, we addressed the hypothesis that the effect of CXC chemokines on CXCR1/2 is important to induce neutrophil migration and inflammatory hypernociception.
Experimental approach:
Mice were treated with a non-competitive allosteric inhibitor of CXCR1/2, DF 2162, and neutrophil influx and inflammatory hypernociception were assessed by myeloperoxidase assay and electronic pressure meter test, respectively, in various models of inflammation.
Key results:
DF 2162 inhibited neutrophil chemotaxis induced by CXCR1/2 ligands but had no effect on CXCL8 binding to neutrophils. A single mutation of the allosteric site at CXCR1 abrogated the inhibitory effect of DF 2162 on CXCL-8-induced chemotaxis. Treatment with DF 2162 prevented influx of neutrophils and inflammatory hypernociception induced by CXCL1 in a dose-dependent manner. The compound inhibited neutrophil influx and inflammatory hypernociception induced by carrageenan, lipopolysaccharide and zymosan, but not hypernociception induced by dopamine and PGE2. DF 2162 had a synergistic effect with indomethacin or the absence of TNFR1 to abrogate carrageenan-induced hypernociception. Treatment with DF 2162 diminished neutrophil influx, oedema formation, disease score and hypernociception in collagen-induced arthritis.
Conclusions and implications:
CXCR1/2 mediates neutrophil migration and is involved in the cascade of events leading to inflammatory hypernociception. In addition to modifying fundamental pathological processes, non-competitive allosteric inhibitors of CXCR1/2 may have the additional benefit of providing partial relief for pain and, hence, may be a valid therapeutic target for further studies aimed at the development of new drugs for the treatment of rheumatoid arthritis.
Keywords:
chemokines, CXCR1/2, arthritis, neutrophil, TNF-
, hyperalgesia
Abbreviations:
IL-1, interleukin-1; KC/CXCL1, keratinocyte-derived chemokine; LPS, lipopolysaccharide; MPO, myeloperoxidase; PGE2, prostaglandin E2; TNF, tumour necrosis factor; TNFR1- /- , TNF receptor type-1 knockout; WT, wild-type
