Translational control of nociception via 4E-binding protein 1
Arkady Khoutorsky,
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,
Nahum Sonenberg
Affiliations
Arkady Khoutorsky
Department of Biochemistry, McGill University, Montréal, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Canada
Unité de neurosciences cellulaires et moléculaire, Institut universitaire en santé mentale de Québec, Québec, Canada
Robert E Sorge
Department of Psychology, McGill University, Montréal, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada
Christos G Gkogkas
Department of Biochemistry, McGill University, Montréal, Canada; Centre for Integrative Physiology and The Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom
Sophie Anne Pawlowski
Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
Seyed Mehdi Jafarnejad
Department of Biochemistry, McGill University, Montréal, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Canada
Mark H Pitcher
National Center for Complementary and Alternative Medicine, National Institutes of Health, Porter Neuroscience Research Center, Maryland, United States
Tommy Alain
Department of Biochemistry, McGill University, Montréal, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Canada
Jimena Perez-Sanchez
Unité de neurosciences cellulaires et moléculaire, Institut universitaire en santé mentale de Québec, Québec, Canada
Eric W Salter
Unité de neurosciences cellulaires et moléculaire, Institut universitaire en santé mentale de Québec, Québec, Canada
Loren Martin
Department of Psychology, McGill University, Montréal, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada
Alfredo Ribeiro-da-Silva
Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
Unité de neurosciences cellulaires et moléculaire, Institut universitaire en santé mentale de Québec, Québec, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada; Department of Psychiatry and Neuroscience, Université Laval, Québec, Canada
Fernando Cervero
Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada; Anesthesia Research Unit, McGill University, Montreal, Canada
Jeffrey S Mogil
Department of Psychology, McGill University, Montréal, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada
Nahum Sonenberg
Department of Biochemistry, McGill University, Montréal, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Canada
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.
