Involvement of epiregulin and epidermal growth factor receptor in pain

The epidermal growth factor receptor (EGFR) belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation and tissue regeneration. In the present study, we demonstrate a novel function for EGFR and its natural ligand, epiregulin (EREG), in pain processing. We show that inhibition of EGFR with clinically used compounds strongly reduces nocifensive behavior in mouse models of inflammatory and chronic pain. EREG enhances nociception through a mechanism that involves the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9. In sensory neurons, EREG potentiates the calcium influx induced by the TRPV1 agonist, capsaicin, but not the TRPA1 agonist, mustard oil. Both the EGFR and EREG genes display genetic association with the development of chronic pain in several clinical cohorts of temporomandibular disorder. Thus, EGFR and EREG may be suitable therapeutic targets for persistent pain conditions.