title: eIF2α phosphorylation controls thermal nociception.
abstract: A response to environmental stress is critical to alleviate cellular injury and maintain cellular homeostasis. Eukaryotic initiation factor 2 (eIF2) is a key integrator of cellular stress responses and an important regulator of mRNA translation. Diverse stress signals lead to the phosphorylation of the α subunit of eIF2 (Ser51), resulting in inhibition of global protein synthesis while promoting expression of proteins that mediate cell adaptation to stress. Here we report that eIF2α is instrumental in the control of noxious heat sensation. Mice with decreased eIF2α phosphorylation (eIF2α+/S51A) exhibit reduced responses to noxious heat. Pharmacological attenuation of eIF2α phosphorylation decreases thermal, but not mechanical, pain sensitivity, whereas increasing eIF2α phosphorylation has the opposite effect on thermal nociception. The impact of eIF2α phosphorylation (p-eIF2α) on thermal thresholds is dependent on the transient receptor potential vanilloid 1. Moreover, we show that induction of eIF2α phosphorylation in primary sensory neurons in a chronic inflammation pain model contributes to thermal hypersensitivity. Our results demonstrate that the cellular stress response pathway, mediated via p-eIF2α, represents a mechanism that could be used to alleviate pathological heat sensation.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC, Canada H3A 1A3; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3; Department of Anesthesia, McGill University, Montreal, QC, Canada H3G 1Y6; Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada H3G 1Y6.
authors.forename: Arkady
authors.initials: A
authors.lastname: Khoutorsky
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada H3G 1Y6; Department of Psychology, McGill University, Montreal, QC, Canada H3A 1B1.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sorge
authors.affiliation: Center for Research in Neuroscience, McGill University, Montreal General Hospital, Montreal, QC, Canada H3G 1A4.
authors.forename: Masha
authors.initials: M
authors.lastname: Prager-Khoutorsky
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada H3G 1Y6; Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada H3G 1Y6.
authors.forename: Sophie Anne
authors.initials: SA
authors.lastname: Pawlowski
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada H3G 1Y6; Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada H3G 1Y6.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Longo
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC, Canada H3A 1A3; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3.
authors.forename: Seyed Mehdi
authors.initials: SM
authors.lastname: Jafarnejad
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC, Canada H3A 1A3; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3.
authors.forename: Soroush
authors.initials: S
authors.lastname: Tahmasebi
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada H3G 1Y6; Department of Psychology, McGill University, Montreal, QC, Canada H3A 1B1.
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: National Center for Complementary and Alternative Medicine, National Institutes of Health, Porter Neuroscience Research Center, MD 20892.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Pitcher
authors.affiliation: Patrick Wild Centre and Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
authors.forename: Christos G
authors.initials: CG
authors.lastname: Gkogkas
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada H3G 1Y6; Department of Physiology, McGill University, Montreal, QC, Canada H3G 1Y6.
authors.forename: Reza
authors.identifier: 0000-0001-8896-5306
authors.initials: R
authors.lastname: Sharif-Naeini
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada H3G 1Y6; Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada H3G 1Y6.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ribeiro-da-Silva
authors.affiliation: Center for Research in Neuroscience, McGill University, Montreal General Hospital, Montreal, QC, Canada H3G 1A4.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Bourque
authors.affiliation: Department of Anesthesia, McGill University, Montreal, QC, Canada H3G 1Y6; Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada H3G 1Y6.
authors.forename: Fernando
authors.initials: F
authors.lastname: Cervero
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada H3G 1Y6; Department of Psychology, McGill University, Montreal, QC, Canada H3A 1B1; jeffrey.mogil@mcgill.ca nahum.sonenberg@mcgill.ca.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC, Canada H3A 1A3; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3; jeffrey.mogil@mcgill.ca nahum.sonenberg@mcgill.ca.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015415:Biomarkers; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057054:Molecular Imaging; D009474:Neurons / Q000378:metabolism; D059225:Nociception; D010146:Pain / Q000209:etiology / Q000378:metabolism; D017288:Pain Threshold; D010766:Phosphorylation; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism; D013312:Stress, Physiological; D050916:TRPV Cation Channels / Q000378:metabolism; D013696:Temperature; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015852:Eukaryotic Initiation Factor-2; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D019892:eIF-2 Kinase; D002118:Calcium
keywords: TRPV1; cellular stress response pathway; eIF2α; pain