Spinal application of TNFα enhances the responses of spinal cord neurons to innocuous and noxious stimulation of the normal knee joint. Spinal application of etanercept which neutralizes TNFα, attenuates the development of inflammation-evoked hyperexcitability suggesting that endogenous TNFα contributes to the development of central sensitization. TNFα acts at two receptors, TNFR1 and TNFR2. In the present study we explored which TNF receptor is involved in the generation of spinal hyperexcitability. We applied to the spinal cord surface antibodies against TNFR1 or TNFR2. To exclude unspecific effects of the antibodies we used in parallel experiments an IgG isotype control. After spinal application of the antibodies we induced an experimental inflammation in the knee joint by intraarticular injection of kaolin and carrageenan and monitored the changes of responses of the spinal neurons to mechanical stimulation of knee, ankle, and paw. Compared to its IgG isotype control the antibody against TNFR1 significantly attenuated the development of inflammation-evoked hyperexcitability. Comparable experiments did not show a difference between the IgG isotype control and the antibody against TNFR2. Thus the effect of TNFα seems to depend on its action at TNFR1. Further preliminary results suggest that the effects of TNFα may also be mediated, at least in part, by an interaction with IL-6. Measurements of IL-6 in superfusates of the lumbar spinal cord with ELISA showed that the release of spinal IL-6 is substantially increased by TNFα application to the spinal cord. Currently we explore whether functional TNFα effects can be reduced by neutralization of IL-6.