The role of proinflammatory cytokines in the generation and maintenance of joint pain

The proinflammatory cytokines tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) not only promote and maintain inflammation, they also contribute to the generation and maintenance of inflammatory pain by acting at nociceptive nerve cells. A large proportion of dorsal root ganglion (DRG) neurons express TNF receptors and receptor units for stimulation with IL‐6. In the rat model of antigen‐induced arthritis (AIA), neutralization of TNF‐α by etanercept and infliximab reduced inflammation‐evoked mechanical hyperalgesia at the inflamed knee joint. This treatment also attenuated the infiltration of macrophages into the DRGs usually observed during the acute phase of AIA. Intra‐articular application of etanercept reduced the responses of C‐fibers to mechanical stimulation of the inflamed joint but did not influence responses to stimulation of the normal joint. Finally, in cultured DRG neurons TNF‐α increased the proportion of neurons that express the TRPV1 receptor and may thus contribute to the generation of inflammation‐evoked thermal hyperalgesia.