It has recently been shown that
epidermal growth factor receptor (EGFR) contributes to the pathogenesis of
pain. We scanned
genetic markers within genes coding for receptors of the EGFR family (EGFR, ERBB2, ERBB3, and ERBB4) and their
ligands (AREG, BTC,
EGF, EPGN, EREG, HBEGF, MUC4, NRG1, NRG2, NRG3, NRG4, and TGFA) for association with self-reported
pain intensity in patients with chronic
facial pain who participated in the
Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cohort. We found that only
epiregulin (EREG) was associated with
pain. The strongest effect was observed for a minor allele at rs6836436 in EREG, which was associated with lower
chronic pain intensity. However, the same allele was associated with higher
facial pain intensity among cases with recent onset of
facial pain. Similar trends were observed in an independent cohort of UK Biobank (UKB) where the minor allele at rs6836436 was associated with a higher number of
acute pain sites but a lower number of
chronic pain sites. Expression quantitative trait loci analyses established rs6836436 as a loss-of-function variant of EREG. Finally, we investigated the functional role of EREG using mouse models of chronic and
acute pain. Injecting mice with an EREG
monoclonal antibody reversed established mechanosensitivity in the complete
Freund's adjuvant and spared nerve injury models of
chronic pain. However, the EREG
monoclonal antibody prolonged
allodynia when administered during the development of complete
Freund's adjuvant-induced mechanosensitivity and enhanced
pain behavior in the
capsaicin model of
acute pain.