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 5

EREG/EGFR increases pain through a PI3K/AKT→mTOR→4E-BP1→eIF4F complex→MMP-9 signaling pathway.

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EREG/EGFR increases pain through a PI3K/AKT→mTOR→4E-BP1→eIF4F complex→MM...
(A) The signaling pathway investigated, with major proteins indicated in black and blocking drugs or mutants shown in red. (B) Treatment with wortmannin (5 μg, i.t.) blocks EREG‑induced increases in late-phase formalin-induced pain behavior (drug × drug: F1,23 = 4.7, P = 0.04). (C) Low doses of rapamycin (5 mg/kg) and CCI 779 (1 mg/kg) block EREG effects without affecting formalin-induced pain per se (rapamycin, drug × drug: F1,27 = 3.6, P = 0.04; CCI 779 drug × drug: F1,28 = 4.2, P = 0.03); higher doses (10 mg/kg) are analgesic (main effects: rapamycin, F1,28 = 22.9, P < 0.001; CCI 779, F1,28 = 30.2, P < 0.001). (D) No effect on EREG increases in formalin-induced pain behavior in SGK1/2 (Rps6kb1/Rps6kb2) double-null mutant mice (Rps6kb1/2–/–; main effect of drug: F1,18 = 25.8, P < 0.001). (E) Lack of EREG effects in 4E-BP1 (Eif4ebp1–/–) null mutant mice (genotype × drug: F1,33 = 7.1, P = 0.01). (F) Treatment with 4EGI-1 (25 μg, i.t.) blocks EREG effects (drug × drug: F1,20 = 7.6, P = 0.01). (G) Treatment with TIMP-1 (4 pmol, i.t.) blocks EREG effects (drug × drug: F1,30 = 5.6, P = 0.02). (H) Lack of EREG effects in MMP-9 null mutants (Mmp9–/–; genotype × drug: F1,20 = 16.1, P = 0.001). In all experiments, EREG was injected at 10 ng i.t. Bars in all graphs represent mean ± SEM for percentage of samples featuring licking/biting behavior; n = 6–8/drug/dose and n = 6–12/drug/genotype (dependent on breeding success). Two-way ANOVA for all panels followed by t test compared with EREG vehicle. *P < 0.05; **P < 0.01; ***P < 0.001, compared with wortmannin, rapamycin, CCI 779, 4EGI-1, or TIMP-1 vehicle, or +/+ genotype. #P < 0.05; ##P < 0.01; ###P < 0.001, compared with rapamycin/CCI 779 vehicle. †P < 0.05 compared with vehicle/vehicle group.