TY - JOUR AU - Martin, Loren J. AU - Smith, Shad B. AU - Khoutorsky, Arkady AU - Magnussen, Claire A. AU - Samoshkin, Alexander AU - Sorge, Robert E. AU - Cho, Chulmin AU - Yosefpour, Noosha AU - Sivaselvachandran, Sivaani AU - Tohyama, Sarasa AU - Cole, Tiffany AU - Khuong, Thang M. AU - Mir, Ellen AU - Gibson, Dustin G. AU - Wieskopf, Jeffrey S. AU - Sotocinal, Susana G. AU - Austin, Jean Sebastien AU - Meloto, Carolina B. AU - Gitt, Joseph H. AU - Gkogkas, Christos AU - Sonenberg, Nahum AU - Greenspan, Joel D. AU - Fillingim, Roger B. AU - Ohrbach, Richard AU - Slade, Gary D. AU - Knott, Charles AU - Dubner, Ronald AU - Nackley, Andrea G. AU - Ribeiro-da-Silva, Alfredo AU - Neely, G. Gregory AU - Maixner, William AU - Zaykin, Dmitri V. AU - Mogil, Jeffrey S. AU - Diatchenko, Luda T1 - Epiregulin and EGFR interactions are involved in pain processing PY - 2017/09/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI87406 VL - 127 IS - 9 UR - https://doi.org/10.1172/JCI87406 SP - 3353 EP - 3366 PB - The American Society for Clinical Investigation ER -