Epiregulin and EGFR interactions are involved in pain processing

J Clin Invest. 2017 Sep 1;127(9):3353-3366. doi: 10.1172/JCI87406. Epub 2017 Aug 7.


The 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 have demonstrated a role for EGFR and its natural ligand, epiregulin (EREG), in pain processing. We show that inhibition of EGFR with clinically available compounds strongly reduced nocifensive behavior in mouse models of inflammatory and chronic pain. EREG-mediated activation of EGFR enhanced nociception through a mechanism involving the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9. Moreover, EREG application potentiated capsaicin-induced calcium influx in a subset of sensory neurons. Both the EGFR and EREG genes displayed a 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.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Behavior, Animal
  • Case-Control Studies
  • Chronic Pain / metabolism*
  • Cohort Studies
  • Drosophila melanogaster
  • Epiregulin / genetics*
  • Epiregulin / physiology*
  • ErbB Receptors / physiology*
  • Female
  • Humans
  • Hyperalgesia / metabolism
  • Inflammation
  • Ligands
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mutation
  • Neurons / metabolism
  • Pain Management
  • Phosphorylation
  • Polymorphism, Single Nucleotide
  • Protein Binding
  • Signal Transduction
  • Young Adult


  • Epiregulin
  • Ereg protein, mouse
  • Ligands
  • EGFR protein, mouse
  • ErbB Receptors
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse