Previous years showed that in clinically relevant pain states a process of spinal neuroinflammation develops which is characterized by the activation of spinal astroglia and microglia and is involved in pain generation by induction of central sensitization (spinal hyperexcitability). Spinal glial cells can release cytokines and other pro-inflammatory mediators. Clinical reports from patients suffering from arthritis suggest that interleukin-6 (IL-6) is one of the most important cytokines that may be involved in pain generation. IL-6 was shown to contribute also to spinal hyperexcitability. Application of biologics to inhibit IL-6 effects, such as Tocilizumab, reduce the pain in early stages of the disease but may not effectively work in the long term, and they also have side effects. Epidermal growth factor receptor (EGFR) plays a role in cancer progression. Therapeutic inhibition of EGFR reduces tumor progression of some cancer types. These studies provided hints that EGFR inhibition may also reduce pain by an action on the nervous system. Interestingly, in tumor cells, there is a functional relationship between IL-6 and EGFR signaling. But there are limited studies available until today about the role of EGFR in nociception and pain. The present study investigated how spinal IL-6 and EGFR activation. In summary, the present study indicates that IL-6 trans-signaling is essential for the induction of hyperexcitability of spinal neurons, and that IL-6 activates EGFR for the maintenance of IL-6 trans-signaling-mediated spinal hyperexcitability. IL-6 and EGF signaling share intracellular signaling mechanisms. The significant upregulation of pEGFR in spinal neurons of G6PI induced arthritis at a late stage, but not at the early stage of arthritis suggests that pain chronification is characterised by increasing EGFR activation. This finding implies that the transition from (acute) IL-6 signaling to EGFR signaling may be of particular importance for pain chronification.