The MNK–eIF4E Signaling Axis Contributes to Injury-Induced Nociceptive Plasticity and the Development of Chronic Pain

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dc.contributor.ISNI0000 0001 3721 4764 (Dussor, G)en_US
dc.contributor.ORCID0000-0001-8579-5540 (Moy, JK)en_US
dc.contributor.ORCID0000-0001-8571-6486 (Black, B)en_US
dc.contributor.ORCID0000-0001-6524-9411 (Kuhn JL)en_US
dc.contributor.ORCID0000-0003-3178-8606 (Barragán-Iglesias, P)en_US
dc.contributor.ORCID0000-0002-6971-6221 (Price, TJ)en_US
dc.contributor.authorMoy, Jamie K.en_US
dc.contributor.authorKhoutorsky, A.en_US
dc.contributor.authorBlack, Brian J.en_US
dc.contributor.authorKuhn, Jasper L.en_US
dc.contributor.authorBarragán-Iglesias, Paulinoen_US
dc.contributor.authorMegat, Salimen_US
dc.contributor.authorBurton, Michael D.en_US
dc.contributor.authorBurgos-Vega, Carolina C.en_US
dc.contributor.authorMelemedjian, O. K.en_US
dc.contributor.authorBoitano, S.en_US
dc.contributor.authorVagner, J.en_US
dc.contributor.authorGkogkas, C. G.en_US
dc.contributor.authorPancrazio, Joseph J.en_US
dc.contributor.authorMogil, J. S.en_US
dc.contributor.authorDussor, Gregoryen_US
dc.contributor.authorSonenberg, N.en_US
dc.contributor.authorPrice, Theodore J.en_US
dc.contributor.utdAuthorMoy, Jamie K.en_US
dc.contributor.utdAuthorAsiedu, Marina N.en_US
dc.contributor.utdAuthorBlack, Brian J.en_US
dc.contributor.utdAuthorKuhn, Jasper L.en_US
dc.contributor.utdAuthorBarragán-Iglesias, Paulinoen_US
dc.contributor.utdAuthorMegat, Salimen_US
dc.contributor.utdAuthorBurton, Michael D.en_US
dc.contributor.utdAuthorBurgos-Vega, Carolina C.en_US
dc.contributor.utdAuthorPancrazio, Joseph J.en_US
dc.contributor.utdAuthorDussor, Gregoryen_US
dc.contributor.utdAuthorPrice, Theodore J.en_US
dc.date.accessioned2018-08-31T15:01:10Z
dc.date.available2018-08-31T15:01:10Z
dc.date.created2017-08-02
dc.description.abstractInjury-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 5β 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 (eIF4ES209A). 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.en_US
dc.description.departmentSchool of Behavioral and Brain Sciencesen_US
dc.identifier.bibliographicCitationMoy, J. K., A. Khoutorsky, M. N. Asiedu, B. J. Black, et al. 2017. "The MNK–eIF4E signaling axis contributes to injury-induced nociceptive plasticity and the development of chronic pain." Journal of Neuroscience 37(31): 7481-7499.en_US
dc.identifier.issn0270-6474en_US
dc.identifier.issue31en_US
dc.identifier.urihttp://hdl.handle.net/10735.1/6044
dc.identifier.volume37en_US
dc.language.isoenen_US
dc.publisherSociety for Neuroscienceen_US
dc.relation.urihttp://dx.doi.org/10.1523/JNEUROSCI.0220-17.2017en_US
dc.rightsCC BY 4.0 (Attribution)en_US
dc.rights©2017 The Authorsen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.source.journalJournal of Neuroscienceen_US
dc.subjectChronic painen_US
dc.subjectGanglia, Spinalen_US
dc.subjectEukaryotic Initiation Factor-4Een_US
dc.subjectMitogen-Activated Protein Kinasesen_US
dc.subjectNociceptorsen_US
dc.subjectCarrageenanen_US
dc.subjectCercosporamideen_US
dc.subjectHeterocyclic Compoundsen_US
dc.subjectInterleukin-6en_US
dc.subjectRNA, Messengeren_US
dc.subjectNerve Growth Factoren_US
dc.subjectProtein-Serine-Threonine Kinasesen_US
dc.subjectAdenosine Triphosphatasesen_US
dc.subjectAtp7a protein, mouseen_US
dc.subjectCalcium Signalingen_US
dc.subjectHypersensitivityen_US
dc.subjectImmunohistochemistryen_US
dc.subjectPeripheral Nerve injuriesen_US
dc.subjectPhenotypeen_US
dc.subjectSpinal Cord Dorsal Hornen_US
dc.subjectGanglia, Spinalen_US
dc.subjectBlotting, Westernen_US
dc.subjectPatch-Clamp Techniquesen_US
dc.subjectMice, Inbred C57BLen_US
dc.subjectDisease Progressionen_US
dc.subjectHyperalgesiaen_US
dc.subjectMetabolismen_US
dc.subjectSignal transductionen_US
dc.subjectAdenosine Triphosphatasesen_US
dc.subjectCation Transport Proteinsen_US
dc.titleThe MNK–eIF4E Signaling Axis Contributes to Injury-Induced Nociceptive Plasticity and the Development of Chronic Painen_US
dc.typeTexten_US
dc.type.genrearticleen_US

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