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 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
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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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 6

EREG and formalin induce phosphorylation of AKT and 4EBP-1 and increase the expression of MMP-9 in lumbar DRG tissue.

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EREG and formalin induce phosphorylation of AKT and 4EBP-1 and increase ...
EREG (10 ng, i.t.) or 5% formalin (20 μl, intraplantar) was injected and lumbar DRG tissue harvested 40 minutes later. Rapamycin was injected 20 minutes before EREG or formalin to mimic behavioral experiment parameters. (A) Representative Western blots showing the phosphorylated and total protein abundance for AKT, 4E-BP1, and S6. The total amount of MMP-9 is also presented. Quantification (phosphorylated/total) for the percentage of fold increase (compared with the control condition) in phosphorylated AKT, 4E‑BP1, and S6 is presented in panels B–D along with the quantification for total MMP-9 (E). Bars represent mean ± SEM for relative change in protein expression. (B) EREG significantly increases the phosphorylation of AKT in DRG tissue. (C) Both formalin and EREG increase the phosphorylation of 4E-BP-1, and the increases are blocked by rapamycin. (D) The phosphorylation of S6 is significantly elevated relative to control tissue by EREG treatment, an increase blocked by rapamycin. (E) Formalin and EREG significantly increase MMP-9 expression, and these increases are blocked by rapamycin. Sample sizes in all groups are n = 4–6. One-way ANOVA for all panels followed by Dunnett’s case-comparison post hoc test. ***P < 0.001 compared with control tissue. †P < 0.05 decrease compared with EREG or formalin alone group. #P < 0.05 increase compared with EREG or formalin alone group.