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

Epiregulin and EGFR interactions are involved in pain processing.

Author information

1
Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.
2
Department of Psychology, University of Toronto Mississauga, Mississauga, Ontario, Canada.
3
Center for Neurosensory Disorders, University of North Carolina, Chapel Hill, North Carolina, USA.
4
Department of Biochemistry and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.
5
Department of Pharmacology and Therapeutics and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.
6
Department of Anesthesia, Faculty of Dentistry and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.
7
Charles Perkins Centre and School of Life and Environmental Sciences, The University of Sydney, Sydney, Australia.
8
Department of Neural and Pain Sciences and Brotman Facial Pain Center, University of Maryland Dental School, Baltimore, Maryland, USA.
9
Department of Community Dentistry and Behavioral Science, University of Florida, Gainesville, Florida, USA.
10
Department of Oral Diagnostic Services, University at Buffalo, Buffalo, New York, USA.
11
Department of Dental Ecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
12
Battelle Memorial Institute, Durham, North Carolina, USA.
13
National Institutes of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.

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.

PMID:
28783046
PMCID:
PMC5669538
DOI:
10.1172/JCI87406
[Indexed for MEDLINE]
Free PMC Article

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