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TitleTranslational control of nociception via 4E-binding protein 1.
Publication TypeJournal Article
Year of Publication2015
AuthorsKhoutorsky, Arkady, Robert P. Bonin, Robert E. Sorge, Christos G. Gkogkas, Sophie Anne Pawlowski, Seyed Mehdi Jafarnejad, Mark H. Pitcher, Tommy Alain, Jimena Perez-Sanchez, Eric W. Salter, Loren Martin, Alfredo Ribeiro-da-Silva, Yves De Koninck, Fernando Cervero, Jeffrey S. Mogil, and Nahum Sonenberg
JournalElife
Volume4
Date Published2015
ISSN2050-084X
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.

DOI10.7554/eLife.12002
Alternate JournalElife
PubMed ID26678009
PubMed Central IDPMC4695384
Grant ListMOP-114994 / / Canadian Institutes of Health Research / Canada