Cooperative role of tumour necrosis factor-α, interleukin-1β and neutrophils in a novel behavioural model that concomitantly demonstrates articular inflammation and hypernociception in mice.

UNLABELLED

BACKGROUND AND PURPOSE; Chronic joint inflammation and pain are the hallmarks of disease in patients with inflammatory arthritis, notably rheumatoid arthritis. The aim of the present study was to investigate the relative contribution of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and neutrophil influx for joint inflammation and nociception in a novel murine model of antigen-induced arthritis (AIA).

EXPERIMENTAL APPROACH

AIA was induced by administration of antigen into knee joint of previously immunized mice. Neutrophil accumulation was determined by counting neutrophils in the joints and assessing myeloperoxidase activity in tissues surrounding the joints. TNF-α, IL-1β and CXCL-1 were measured by elisa. Mechanical hypernociception was assessed in parallel, using an electronic pressure meter.

KEY RESULTS

Hypernociception was dependent on antigen dose and the time after its administration; it was prevented by treatment with morphine and associated with neutrophil infiltration and local production of TNF-α, IL-1β and CXCL-1. Administration of a chimeric monoclonal antibody to TNF-α (infliximab) or IL-1receptor antagonist prevented neutrophil influx and hypernociception, and this was comparable to the effects of dexamethasone. Treatment with fucoidin (a leucocyte adhesion inhibitor) greatly suppressed neutrophil influx and local production of TNF-α and IL-1β, and hypernociception.

CONCLUSIONS AND IMPLICATIONS

In conclusion, the present study describes a new model that allows for the concomitant evaluation of articular hypernociception and inflammation. Using this system, we demonstrated that a positive feedback loop involving neutrophil influx and the pro-inflammatory cytokines TNF-α and IL-1β is necessary for articular hypernociception after antigen challenge of immunized mice.