Epiregulin and EGFR interactions are involved in pain processing

Loren J. Martin(University of Toronto), Shad B. Smith(University of North Carolina at Chapel Hill), Arkady Khoutorsky(McGill University), Claire Magnussen(McGill University Health Centre), Alexander Samoshkin(McGill University), Robert E. Sorge(McGill University), Chulmin Cho(University of Toronto), Noosha Yosefpour(McGill University Health Centre), Sivaani Sivaselvachandran(University of Toronto), Sarasa Tohyama(University of Toronto), Tiffany Cole(The University of Sydney), Thang M. Khuong(The University of Sydney), Ellen Mir(University of North Carolina at Chapel Hill), Dustin G. Gibson(University of North Carolina at Chapel Hill), Jeffrey S. Wieskopf(McGill University), Susana G. Sotocinal(McGill University), Jean S. Austin(McGill University), Carolina B. Meloto(McGill University), Joseph H. Gitt(University of North Carolina at Chapel Hill), Christos G. Gkogkas(McGill University), Nahum Sonenberg(McGill University), Joel D. Greenspan(University of Maryland, Baltimore), Roger B. Fillingim(University of Florida), Richard Ohrbach(University at Buffalo, State University of New York), Gary D. Slade(University of North Carolina at Chapel Hill), Charles Knott(Battelle), Ronald Dubner(University of Maryland, Baltimore), Andrea G. Nackley(University of North Carolina at Chapel Hill), Alfredo Ribeiro‐da‐Silva(McGill University Health Centre), G. Gregory Neely(The University of Sydney), William Maixner(University of North Carolina at Chapel Hill), Dmitri V. Zaykin(National Institute of Environmental Health Sciences), Jeffrey S. Mogil(McGill University), Luda Diatchenko(McGill University)
Journal of Clinical Investigation
August 6, 2017
10.1172/jci87406
Cited by 118Open Access
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Abstract

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.

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