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Elife. 2015 Dec 18;4. pii: e12002. doi: 10.7554/eLife.12002.

Translational control of nociception via 4E-binding protein 1.

Author information

1
Department of Biochemistry, McGill University, Montréal, Canada.
2
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Canada.
3
Unité de neurosciences cellulaires et moléculaire, Institut universitaire en santé mentale de Québec, Québec, Canada.
4
Department of Psychology, McGill University, Montréal, Canada.
5
Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada.
6
Centre for Integrative Physiology and The Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom.
7
Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
8
National Center for Complementary and Alternative Medicine, National Institutes of Health, Porter Neuroscience Research Center, Maryland, United States.
9
Department of Psychiatry and Neuroscience, Université Laval, Québec, Canada.
10
Anesthesia Research Unit, McGill University, Montreal, Canada.

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.

KEYWORDS:

biochemistry; eIF4F complex; mRNA translation; mouse; neuroscience; pain

PMID:
26678009
PMCID:
PMC4695384
DOI:
10.7554/eLife.12002
[Indexed for MEDLINE]
Free PMC Article

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