Treatment with biologicals neutralizing TNFα was shown to reduce inflammatory hyperalgesia in experimental (Böttger et al. 2008) and human arthritis (Hess et al. 2011). While in the periphery TNFa induced long-lasting sensitization of joint afferents (Richter et al. 2010) the role of spinal TNFα in inflammation-evoked spinal hyperexcitability is possibly indirect because we detected IL-6 after TNFα application in the spinal supernatant. We tested whether spinal effects of TNFα depend on IL-6. We recorded from nociceptive spinal neurons with input from the knee joint in anesthetized rats. We used either normal rats or animals with acute Kaolin/Carrageenan inflammation in the knee as a model of arthritis. The leg was mechanically stimulated at the knee, ankle and paw with innocuous and noxious intensity. During development of inflammation spinal application of an antibody to TNFR1 but not to TNFR2 prevented spinal hyperexcitability. Hyperexcitability during acute inflammation was not reduced by etanercept. When TNFα was applied to the surface of the spinal cord responses to stimulation of the leg increased. Spinal co-application of TNFα and spg130 lead to significant smaller responses to stimulation than application of TNFα alone. In summary TNFα induces spinal hyperexcitability via activation of TNFR1 receptors and subsequent release of spinal IL-6 which is overtaking the maintenance of spinal hyperexcitability
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