eIF2α phosphorylation controls thermal nociception

Arkady Khoutorsky, Robert E. Sorge, Masha Prager-Khoutorsky, Sophie Anne Pawlowski, Geraldine Longo, Seyed Mehdi Jafarnejad, Soroush Tahmasebi, Loren Martin, Mark H. Pitcher, Christos Gkogkas, Reza Sharif-Naeini, Reza Sharif-Naeini, Alfredo Ribeiro-da-Silva, Charles W. Bourque, Fernando Cervero, Jeffrey S. Mogil, Nahum Sonenberg

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)11949–11954
JournalProceedings of the National Academy of Sciences
Issue number42
Early online date3 Oct 2016
Publication statusPublished - 18 Oct 2016


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