Ephrin-B2 Promotes Nociceptive Plasticity and Hyperalgesic Priming Through EphB2-MNK-eIF4E Signaling in Both Mice and Humans

Authors

Eric David
Muhammad Saad Yousuf
Hao-Ruei Mei
Ashita Jain
Sharada Krishnagiri
Hajira Elahi
Rupali Venkatesan
Kolluru Srikanth, Thomas Jefferson University
Gregory Dussor
Matthew Dalva, Thomas Jefferson UniversityFollow
Theodore Price

Document Type

Article

Publication Date

6-24-2024

Comments

This article is the author's final published version in Pharmacological Research, Volume 206, 2024, Article number 107284.

The published version is available at https://doi.org/10.1016/j.phrs.2024.107284.

Copyright © 2024 The Author(s)

Abstract

Ephrin-B-EphB signaling can promote pain through ligand-receptor interactions between peripheral cells, like immune cells expressing ephrin-Bs, and EphB receptors expressed by DRG neurons. Previous studies have shown increased ephrin-B2 expression in peripheral tissues like synovium of rheumatoid and osteoarthritis patients, indicating the clinical significance of this signaling. The primary goal of this study was to understand how ephrin-B2 acts on mouse and human DRG neurons, which express EphB receptors, to promote pain and nociceptor plasticity. We hypothesized that ephrin-B2 would promote nociceptor plasticity and hyperalgesic priming through MNK-eIF4E signaling, a critical mechanism for nociceptive plasticity induced by growth factors, cytokines and nerve injury. Both male and female mice developed dose-dependent mechanical hypersensitivity in response to ephrin-B2, and both sexes showed hyperalgesic priming when challenged with PGE₂ injection either to the paw or the cranial dura. Acute nociceptive behaviors and hyperalgesic priming were blocked in mice lacking MNK1 (Mknk1 knockout mice) and by eFT508, a specific MNK inhibitor. Sensory neuron-specific knockout of EphB2 using Pirt-Cre demonstrated that ephrin-B2 actions require this receptor. In Ca²⁺-imaging experiments on cultured DRG neurons, ephrin-B2 treatment enhanced Ca²⁺ transients in response to PGE₂ and these effects were absent in DRG neurons from MNK1^-/- and EphB2-Pirt^Cre mice. In experiments on human DRG neurons, ephrin-B2 increased eIF4E phosphorylation and enhanced Ca²⁺ responses to PGE₂ treatment, both blocked by eFT508. We conclude that ephrin-B2 acts directly on mouse and human sensory neurons to induce nociceptor plasticity via MNK-eIF4E signaling, offering new insight into how ephrin-B signaling promotes pain.

Recommended Citation

David, Eric; Yousuf, Muhammad Saad; Mei, Hao-Ruei; Jain, Ashita; Krishnagiri, Sharada; Elahi, Hajira; Venkatesan, Rupali; Srikanth, Kolluru; Dussor, Gregory; Dalva, Matthew; and Price, Theodore, "Ephrin-B2 Promotes Nociceptive Plasticity and Hyperalgesic Priming Through EphB2-MNK-eIF4E Signaling in Both Mice and Humans" (2024). Department of Neuroscience Faculty Papers. Paper 84.
https://jdc.jefferson.edu/department_neuroscience/84

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Language

English