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Review ArticleReview Article

Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain

Muhammad Saad Yousuf, Stephanie I. Shiers, James J. Sahn and Theodore J. Price
Robert Dantzer, ASSOCIATE EDITOR
Pharmacological Reviews January 2021, 73 (1) 59-88; DOI: https://doi.org/10.1124/pharmrev.120.000030
Muhammad Saad Yousuf
Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas (M.S.Y., S.I.S., T.J.P.) and 4E Therapeutics Inc, Austin, Texas (J.J.S.)
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Stephanie I. Shiers
Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas (M.S.Y., S.I.S., T.J.P.) and 4E Therapeutics Inc, Austin, Texas (J.J.S.)
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James J. Sahn
Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas (M.S.Y., S.I.S., T.J.P.) and 4E Therapeutics Inc, Austin, Texas (J.J.S.)
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Theodore J. Price
Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas (M.S.Y., S.I.S., T.J.P.) and 4E Therapeutics Inc, Austin, Texas (J.J.S.)
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Robert Dantzer
Roles: ASSOCIATE EDITOR
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Abstract

Dysfunction in regulation of mRNA translation is an increasingly recognized characteristic of many diseases and disorders, including cancer, diabetes, autoimmunity, neurodegeneration, and chronic pain. Approximately 50 million adults in the United States experience chronic pain. This economic burden is greater than annual costs associated with heart disease, cancer, and diabetes combined. Treatment options for chronic pain are inadequately efficacious and riddled with adverse side effects. There is thus an urgent unmet need for novel approaches to treating chronic pain. Sensitization of neurons along the nociceptive pathway causes chronic pain states driving symptoms that include spontaneous pain and mechanical and thermal hypersensitivity. More than a decade of preclinical research demonstrates that translational mechanisms regulate the changes in gene expression that are required for ongoing sensitization of nociceptive sensory neurons. This review will describe how key translation regulation signaling pathways, including the integrated stress response, mammalian target of rapamycin, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase–interacting kinases, impact the translation of different subsets of mRNAs. We then place these mechanisms of translation regulation in the context of chronic pain states, evaluate currently available therapies, and examine the potential for developing novel drugs. Considering the large body of evidence now published in this area, we propose that pharmacologically manipulating specific aspects of the translational machinery may reverse key neuronal phenotypic changes causing different chronic pain conditions. Therapeutics targeting these pathways could eventually be first-line drugs used to treat chronic pain disorders.

Significance Statement Translational mechanisms regulating protein synthesis underlie phenotypic changes in the sensory nervous system that drive chronic pain states. This review highlights regulatory mechanisms that control translation initiation and how to exploit them in treating persistent pain conditions. We explore the role of mammalian/mechanistic target of rapamycin and mitogen-activated protein kinase–interacting kinase inhibitors and AMPK activators in alleviating pain hypersensitivity. Modulation of eukaryotic initiation factor 2α phosphorylation is also discussed as a potential therapy. Targeting specific translation regulation mechanisms may reverse changes in neuronal hyperexcitability associated with painful conditions.

Footnotes

  • This work was supported by Postdoctoral Fellowship Program of Natural Sciences and Engineering Research Council of Canada and by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01-NS102161], [Grant R01-NS065926], and [Grant U44-NS115692].

  • The authors declare financial relationships. J.J.S. is an employee of 4E Therapeutics, and T.J.P. is a cofounder of 4E Therapeutics.

  • https://doi.org/10.1124/pharmrev.120.000030.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 73 (1)
Pharmacological Reviews
Vol. 73, Issue 1
1 Jan 2021
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Review ArticleReview Article

Targeting Translation for Pain

Muhammad Saad Yousuf, Stephanie I. Shiers, James J. Sahn and Theodore J. Price
Pharmacological Reviews January 1, 2021, 73 (1) 59-88; DOI: https://doi.org/10.1124/pharmrev.120.000030

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Review ArticleReview Article

Targeting Translation for Pain

Muhammad Saad Yousuf, Stephanie I. Shiers, James J. Sahn and Theodore J. Price
Pharmacological Reviews January 1, 2021, 73 (1) 59-88; DOI: https://doi.org/10.1124/pharmrev.120.000030
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  • Article
    • Visual Overview
    • Abstract
    • I. The Unmet Need of Analgesics
    • II. Physiology of Pain
    • III. Why Target Translation for Pain Treatment
    • IV. Basics of Gene Expression
    • V. Regulation of mRNA Translation—Linking Signaling to Translation of Subsets of mRNAs
    • VI. Targeting Translation in Chronic Pain
    • VII. Future Opportunities
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