Treatment with DF 2162, a non‐competitive allosteric inhibitor of CXCR1/2, diminishes neutrophil influx and inflammatory hypernociception in mice

Abstract

.r.ma s.p.a., L'Aquila, Italy 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 PGE 2 . 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.

Cytokine biomarkers and chronic pain: Association of genes, transcription, and circulating proteins with temporomandibular disorders and widespread palpation tenderness

“…Administration of IL-8 produces dose-dependent hyperalgesia, which is mediated by sympathetic amines that sensitize nociceptors [3; 17; 20]. In animals, administration of anti-IL-8 serum [17; 18] or an allosteric inhibitor of CXCR1 and CXCR2 receptors [19] reduces the severity of persistent pain. In fibromyalgia patients, biopsychosocial and exercise therapies that reduce circulating IL-8 levels, also reduce pain [71; 94].…”

In VitroTNF-αInhibitory Activity of Brazilian Plants and Anti-Inflammatory Effect ofStryphnodendron adstringensin an Acute Arthritis Model

“…The organic and aqueous fractions of C. lineatifolia, S. adstringens , and T. glabrescens had their anti-inflammatory activity assayed, as described by Cunha et al [28]. Female Swiss mice (6 weeks old), weighing between 28 and 32 g, obtained from the Animal Housing Unit of the Faculty of Pharmacy, UFMG, were employed in the experiments.…”

Genes, molecules and patients—Emerging topics to guide clinical pain research

“…In rodent models of inflammatory pain that are induced with the injection of antigens, including zymosan, lipopolysaccharide (LPS) or carageenan, the accumulation of neutrophils in the treated tissue is critical for the development of evoked hypersensitivity and standard inflammatory markers (Cunha et al, 2008). In the intact uninjured nerve there in an absence of neutrophils, however in rodent models of neuropathy (including partial nerve ligation (Zuo et al, 2003), sciatic nerve crush (Perry et al, 1987) and chronic constriction injury (Clatworthy et al, 1995)), neutrophils migrate and infiltrate the site of the nerve lesion.…”