Epiregulin and EGFR interactions are involved in pain processing
Loren J. Martin, … , Jeffrey S. Mogil, Luda Diatchenko
Loren J. Martin, … , Jeffrey S. Mogil, Luda Diatchenko
Published August 7, 2017
Citation Information: J Clin Invest. 2017;127(9):3353-3366. https://doi.org/10.1172/JCI87406.
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Research Article Neuroscience

Epiregulin and EGFR interactions are involved in pain processing

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.

Authors

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 G. Gibson, Jeffrey S. Wieskopf, Susana G. Sotocinal, Jean Sebastien Austin, Carolina B. Meloto, Joseph H. Gitt, Christos Gkogkas, Nahum Sonenberg, Joel D. 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

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Figure 2

Spinally administered EREG, but not other EGFR ligands, produces hypersensitivity.

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Spinally administered EREG, but not other EGFR ligands, produces hyperse...
(A) Significant and dose‑dependent hypersensitivity from EREG (2-way ANOVA, F3,26 = 6.8, P = 0.002), but not betacellulin, amphiregulin, EGF, or TGF-α (all P values are greater than 0.50) in the late phase (10–60 minutes) of the formalin test. Symbols represent mean ± SEM for percentage of samples featuring licking/biting behavior; n = 6–8/drug/dose. EREG enhancement of formalin-induced licking was equivalent to that of NGF; 2-way ANOVA, F3,22 = 10.9, P < 0.001. (B) EREG (10 ng, i.t.) increases nocifensive behavior when coadministered with intraplantar injections of the TRPV1 agonist capsaicin (2-tailed t test, t10 = 3.4, P = 0.01), but not the TRPA1 agonist mustard oil (2-tailed t test, t13 = 0.34, P = 0.70). Bars represent mean ± SEM for duration of licking behavior over 10 minutes after injection; n = 6‑8/algogen/drug. (C) The TRPV1 antagonist AMG 9810 (30 mg/kg, i.p.), but not the TRPA1 antagonist HC-030031 (30 mg/kg, i.p.), blocks EREG-induced hyperalgesia during the formalin test (2-way ANOVA, drug × antagonist interaction: F2,38 = 7.2, P = 0.002). Bars as in graph A; n = 7-8/group. (D) EREG (10 ng) increases thermal sensitivity by itself (2-tailed paired t test, t10 = 2.6, P = 0.03). Bars represent mean ± SEM for latency to withdraw from a noxious thermal stimulus before (baseline) and 30 minutes after injection; n = 6/drug. (E) EREG (10 ng) increases mechanical sensitivity by itself (2-tailed paired t test, t10 = 2.2, P = 0.05). Bars represent mean ± SEM for hind paw–withdrawal threshold (g) before (baseline) and 30 minutes after injection; n = 6/drug. (F) ΔEGFR mutants have higher baseline pain sensitivity to formalin than WT (vehicle groups), but no longer respond to EREG (10 ng, i.t.). Bars as in graph E; n = 7–8/genotype/drug. For all panels, *P < 0.05; **P < 0.01; ***P < 0.001 compared with vehicle (0) by Dunnett’s case-comparison post hoc test or t test as indicated. #P < 0.01 compared with other genotype (in F) by Dunnett’s case-comparison post hoc test.