Epiregulin and EGFR interactions are involved in pain processing

Loren J. Martin, Shad B. Smith, Arkady Khoutorsky, Claire A. Magnussen, Alexander Samoshkin, Robert E. Sorge, Chulmin Cho, Noosha Yosefpour, Sivaani Sivaselvachandran, Sarasa Tohyama, Tiffany Cole, Thang M. Khuong, Ellen Mir, Dustin Gibson, Jeffrey S. Wieskopf, Susana G. Sotocinal, Jean Sebastien Austin, Carolina B. Meloto, Joseph H. Gitt, Christos GkogkasNahum Sonenberg, Joel Daniel Greenspan, Roger B. Fillingim, Richard Ohrbach, Gary D. Slade, Charles Knott, Ronald Dubner, Andrea G. Nackley, Alfredo Ribeiro-Da-Silva, G. Gregory Neely, William Maixner, Dmitri V. Zaykin, Jeffrey S. Mogil, Luda Diatchenko

Research output: Contribution to journalArticle

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. 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.

Original languageEnglish (US)
Pages (from-to)3353-3366
Number of pages14
JournalJournal of Clinical Investigation
Volume127
Issue number9
DOIs
StatePublished - Sep 1 2017
Externally publishedYes

Fingerprint

Pain
Chronic Pain
Ligands
erbB-1 Genes
Temporomandibular Joint Disorders
Nociception
Capsaicin
Matrix Metalloproteinase 9
Sensory Receptor Cells
Phosphatidylinositol 3-Kinases
Protein-Tyrosine Kinases
Regeneration
Cell Proliferation
Calcium
Epiregulin
Growth
Therapeutics
ErbB Receptors
Inhibition (Psychology)

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Martin, L. J., Smith, S. B., Khoutorsky, A., Magnussen, C. A., Samoshkin, A., Sorge, R. E., ... Diatchenko, L. (2017). Epiregulin and EGFR interactions are involved in pain processing. Journal of Clinical Investigation, 127(9), 3353-3366. https://doi.org/10.1172/JCI87406

Epiregulin and EGFR interactions are involved in pain processing. / Martin, Loren J.; Smith, Shad B.; Khoutorsky, Arkady; Magnussen, Claire A.; Samoshkin, Alexander; Sorge, Robert E.; Cho, Chulmin; Yosefpour, Noosha; Sivaselvachandran, Sivaani; Tohyama, Sarasa; Cole, Tiffany; Khuong, Thang M.; Mir, Ellen; Gibson, Dustin; Wieskopf, Jeffrey S.; Sotocinal, Susana G.; Austin, Jean Sebastien; Meloto, Carolina B.; Gitt, Joseph H.; Gkogkas, Christos; Sonenberg, Nahum; Greenspan, Joel Daniel; Fillingim, Roger B.; Ohrbach, Richard; Slade, Gary D.; Knott, Charles; Dubner, Ronald; Nackley, Andrea G.; Ribeiro-Da-Silva, Alfredo; Neely, G. Gregory; Maixner, William; Zaykin, Dmitri V.; Mogil, Jeffrey S.; Diatchenko, Luda.

In: Journal of Clinical Investigation, Vol. 127, No. 9, 01.09.2017, p. 3353-3366.

Research output: Contribution to journalArticle

Martin, LJ, Smith, SB, Khoutorsky, A, Magnussen, CA, Samoshkin, A, Sorge, RE, Cho, C, Yosefpour, N, Sivaselvachandran, S, Tohyama, S, Cole, T, Khuong, TM, Mir, E, Gibson, D, Wieskopf, JS, Sotocinal, SG, Austin, JS, Meloto, CB, Gitt, JH, Gkogkas, C, Sonenberg, N, Greenspan, JD, Fillingim, RB, Ohrbach, R, Slade, GD, Knott, C, Dubner, R, Nackley, AG, Ribeiro-Da-Silva, A, Neely, GG, Maixner, W, Zaykin, DV, Mogil, JS & Diatchenko, L 2017, 'Epiregulin and EGFR interactions are involved in pain processing', Journal of Clinical Investigation, vol. 127, no. 9, pp. 3353-3366. https://doi.org/10.1172/JCI87406
Martin LJ, Smith SB, Khoutorsky A, Magnussen CA, Samoshkin A, Sorge RE et al. Epiregulin and EGFR interactions are involved in pain processing. Journal of Clinical Investigation. 2017 Sep 1;127(9):3353-3366. https://doi.org/10.1172/JCI87406
Martin, Loren J. ; Smith, Shad B. ; Khoutorsky, Arkady ; Magnussen, Claire A. ; Samoshkin, Alexander ; Sorge, Robert E. ; Cho, Chulmin ; Yosefpour, Noosha ; Sivaselvachandran, Sivaani ; Tohyama, Sarasa ; Cole, Tiffany ; Khuong, Thang M. ; Mir, Ellen ; Gibson, Dustin ; Wieskopf, Jeffrey S. ; Sotocinal, Susana G. ; Austin, Jean Sebastien ; Meloto, Carolina B. ; Gitt, Joseph H. ; Gkogkas, Christos ; Sonenberg, Nahum ; Greenspan, Joel Daniel ; Fillingim, Roger B. ; Ohrbach, Richard ; Slade, Gary D. ; Knott, Charles ; Dubner, Ronald ; Nackley, Andrea G. ; Ribeiro-Da-Silva, Alfredo ; Neely, G. Gregory ; Maixner, William ; Zaykin, Dmitri V. ; Mogil, Jeffrey S. ; Diatchenko, Luda. / Epiregulin and EGFR interactions are involved in pain processing. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 9. pp. 3353-3366.
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