Injury-induced sensitization of nociceptors contributes to pain states and the development of chronic pain. Inhibiting activity-dependent mRNA translation through mechanistic target of rapamycin and mitogen-activated protein kinase (MAPK) pathways blocks the development of nociceptor sensitization. These pathways convergently signal to the eukaryotic translation initiation factor (eIF) 4F complex to regulate the sensitization of nociceptors, but the details of this process are ill defined. Here we investigated the hypothesis that phosphorylation of the 5' cap-binding protein eIF4E by its specific kinase MAPK interacting kinases (MNKs) 1/2 is a key factor in nociceptor sensitization and the development of chronic pain. Phosphorylation of ser209 on eIF4E regulates the translation of a subset of mRNAs. We show that pronociceptive and inflammatory factors, such as nerve growth factor (NGF), interleukin-6 (IL-6), and carrageenan, produce decreased mechanical and thermal hypersensitivity, decreased affective pain behaviors, and strongly reduced hyperalgesic priming in mice lacking eIF4E phosphorylation (eIF4E(S209A)). Tests were done in both sexes, and no sex differences were found. Moreover, in patch-clamp electrophysiology and Ca2+ imaging experiments on dorsal root ganglion neurons, NGF-and IL-6-induced increases in excitability were attenuated in neurons from eIF4ES209A mice. These effects were recapitulated in Mnk1/2(-/-) mice and with the MNK1/2 inhibitor cercosporamide. We also find that cold hypersensitivity induced by peripheral nerve injury is reduced in eIF4ES209A and Mnk1/2 (-/-) mice and following cercosporamide treatment. Our findings demonstrate that the MNK1/2-eIF4E signaling axis is an important contributing factor to mechanisms of nociceptor plasticity and the development of chronic pain.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/625494 |
| Date | 02 August 2017 |
| Creators | Moy, Jamie K., Khoutorsky, Arkady, Asiedu, Marina N., Black, Bryan J., Kuhn, Jasper L., Barragán-Iglesias, Paulino, Megat, Salim, Burton, Michael D., Burgos-Vega, Carolina C., Melemedjian, Ohannes K., Boitano, Scott, Vagner, Josef, Gkogkas, Christos G., Pancrazio, Joseph J., Mogil, Jeffrey S., Dussor, Gregory, Sonenberg, Nahum, Price, Theodore J. |
| Contributors | Univ Arizona, Collaborat Res Inst Bio5, Univ Arizona, Dept Pharmacol, Univ Arizona, Dept Physiol |
| Publisher | SOC NEUROSCIENCE |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | Copyright © 2017 the authors. |
| Relation | http://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.0220-17.2017 |
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