Translational control of nociception via 4E-binding protein 1

A Khoutorsky, RP Bonin, RE Sorge, CG Gkogkas, SA Pawlowski, SM Jafarnejad, MH Pitcher, T Alain, J Perez-Sanchez, EW Salter, L Martin, Alfredo Ribeiro-da-Silva, Yves De Koninck, Fernando Cervero, Jeffrey S. Mogil, N Sonenberg

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    Abstract

    Activation of the mechanistic/mammalian target of rapamycin (mTOR) kinase in models of acute and chronic pain is strongly implicated in mediating enhanced translation and hyperalgesia. However, the molecular mechanisms by which mTOR regulates nociception remain unclear. Here we show that deletion of the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a major mTOR downstream effector, which represses eIF4E activity and cap-dependent translation, leads to mechanical, but not thermal pain hypersensitivity. Mice lacking 4E-BP1 exhibit enhanced spinal cord expression of neuroligin 1, a cell-adhesion postsynaptic protein regulating excitatory synapse function, and show increased excitatory synaptic input into spinal neurons, and a lowered threshold for induction of synaptic potentiation. Pharmacological inhibition of eIF4E or genetic reduction of neuroligin 1 levels normalizes the increased excitatory synaptic activity and reverses mechanical hypersensitivity. Thus, translational control by 4E-BP1 downstream of mTOR effects the expression of neuroligin 1 and excitatory synaptic transmission in the spinal cord, and thereby contributes to enhanced mechanical nociception.
    Original languageEnglish
    Article numbere12002
    Number of pages18
    JournaleLife
    DOIs
    Publication statusPublished - 18 Dec 2015

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    Khoutorsky, A., Bonin, RP., Sorge, RE., Gkogkas, CG., Pawlowski, SA., Jafarnejad, SM., Pitcher, MH., Alain, T., Perez-Sanchez, J., Salter, EW., Martin, L., Ribeiro-da-Silva, A., De Koninck, Y., Cervero, F., Mogil, J. S., & Sonenberg, N. (2015). Translational control of nociception via 4E-binding protein 1. eLife, [e12002]. https://doi.org/10.7554/elife.12002