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 September 1, 2017; First 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 1

EGFR antagonists produce analgesia and EREG produces hyperalgesia in the mouse.

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EGFR antagonists produce analgesia and EREG produces hyperalgesia in the...
(A) No sedation or ataxia (2-way ANOVA, drug × repeated measures: F12,80 = 0.5, P = 0.88) produced by high doses of EGFR antagonists. Symbols represent mean ± SEM for latency to fall off rotarod at each time point; n = 6–8/drug. (B) No effect of EGFR antagonists on acute thermal pain measured using the radiant heat paw-withdrawal test (2-way ANOVA, drug × repeated measures: F3,19 = 2.3, P = 0.10). Bars represent mean ± SEM for latency to withdraw from a noxious thermal stimulus before (baseline) and 30 minutes after injection; n = 5–6/drug. (C) No effect of EGFR antagonists on acute mechanical sensation using the von Frey test (2-way ANOVA, drug × repeated measures: F3,19 = 0.3, P = 0.80). Bars represent mean ± SEM for hind paw withdrawal threshold (g) before (baseline) and 30 minutes after injection; n = 5–6/drug. (D) EGFR antagonists produce analgesia during the formalin test in both the early (0–10 minutes; 1-way ANOVA, F3,29 = 7.2, P = 0.001) and late (10–60 minutes; 1-way ANOVA, F3,29 = 15.9, P < 0.001) phases. Bars represent mean ± SEM for percentage of samples featuring licking/biting behavior; n = 7–9/drug. (E) Dose‑dependent analgesia from EGFR antagonists and morphine on the late‑phase formalin test; symbols represent mean ± SEM for percentage of samples featuring licking/biting behavior; n = 6–8/drug/dose. See Supplemental Table 1 for half-maximal analgesic doses and 95% confidence intervals. (F) EGFR antagonists reverse thermal hypersensitivity induced by carrageenan (2-way ANOVA, drug × repeated measures: F9,57 = 2.8, P = 0.01). Symbols represent mean ± SEM for latency to withdraw from a noxious thermal stimulus before carrageenan (Pre‑BL), 3 hours after carrageenan (0), and 20–60 minutes after drug administration; n = 5–6/drug. (G) EGFR antagonists dose‑dependently reverse mechanical allodynia induced by CFA (3 days after injection). Symbols represent mean ± SEM for percentage of maximum possible antiallodynia (i.e., reversal back to baseline withdrawal thresholds at all post-drug time points; see Methods); n = 5–6/drug/dose. (H) EGFR antagonists dose‑dependently reverse mechanical allodynia induced by SNI (7 days after surgery). Symbols as in G; n = 5–6/drug/dose. See Supplemental Table 2 for half‑maximal analgesic doses and 95% confidence intervals relevant to graphs in G and H. (I) AG 1478 reverses mechanical allodynia induced by CCI (14 days after surgery); n = 6/drug (2-way ANOVA, drug × repeated measures: F4,40 = 2.6, P = 0.02). *P < 0.05; **P < 0.01; ***P < 0.001 compared with vehicle (0) group by Dunnett’s case-comparison post hoc test.