TY - JOUR
T1 - Epiregulin and EGFR interactions are involved in pain processing
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
N1 - Funding Information:
The authors would like thank Oskar Laur for creating EREG-expressing constructs at the Custom Cloning Core Facility, Emory University. This research was supported by the Canadian Institutes for Health Research (CIHR) (NS, ARDS, and JSM), the NIH (JDG, RBF, RO, GDS, CK, RD, WM, and LD), the Australian National Health and Medical Research Council (TC, TMK, GGN), and the Louise and Alan Edwards Foundation (JSM). LJM was supported by postdoctoral fellowships from CIHR and the Canadian Pain Society.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - 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. EREGmediated 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.
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. EREGmediated 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.
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U2 - 10.1172/JCI87406
DO - 10.1172/JCI87406
M3 - Article
C2 - 28783046
AN - SCOPUS:85028943267
SN - 0021-9738
VL - 127
SP - 3353
EP - 3366
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -