Low back pain and sciatica after disc herniation may be caused by mechanical compression of the nerve roots, but also by the release of pro-inflammatory agents and growth factors from the nucleus pulposus (NP) of the herniated disc. In the present study the functional changes in nociceptive signaling due to disc herniation were investigated. NP tissue was harvested from tail vertebrae and incubated in cell medium to examine if NP cells were able to secrete epiregulin (EREG), a member of the epidermal growth factor (EGF) family. Extracellular single-cell recordings in the spinal dorsal horn (DH) were performed to investigate the effect of EREG on neuronal excitability. The expression of EREG and its receptors were examined by qPCR in NP tissue, DH of the spinal cord, and the dorsal root ganglions (DRG). The present data demonstrated that EREG may be released after disc herniation from NP tissue. Directly administration of EREG onto the spinal dorsal nerve roots induced a decrease in responsiveness to electrical stimuli, but a pronounced increase in spontaneous activity in nociceptive neurons. A significant up-regulation of the gene encoding EREG was observed in the DH, when NP tissue was exposed to the spinal dorsal nerve roots. The EREG receptors EGFR and HER4 were up-regulated in NP tissue and DH tissue, whereas HER3 was up-regulated in DRGs. Taken together, our findings suggest that EREG signaling through its receptors may induce sensory abnormalities and pain hypersensitivity following a disc herniation.