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eIF4E phosphorylation modulates pain and neuroinflammation in the aged

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Abstract

The aged population has a higher probability of developing chronic pain from acute insults because of age-associated low-grade inflammation. Several emerging studies have shown a crucial role of cap-dependent translation in the development of chronic pain in young adult animals; however, its role in the aged has never been reported. Acute and chronic inflammatory responses, including pain, are altered over age, and understanding how cap-dependent translation can represent an important and druggable pathway is imperative for understanding its therapeutic potential. Here we have tested how an inflammatory stimulus, complete Freund’s adjuvant (CFA), affects spontaneous and evoked pain, as well as inflammation in young versus aged mice that lack functional cap-dependent translation machinery (eukaryotic translation initiation factor 4E (eIF4E)) compared with age-matched wild-type (WT) mice. Interestingly, we found that CFA-induced acute pain and inflammation are modulated by eIF4E phosphorylation in aged but not young animals. Aged transgenic animals showed attenuated paw temperature and inflammation, as well as a mitigation in the onset and quicker resolution in mechanical and thermal hypersensitivity. We found that levels of interleukin (IL)-1β and tumor necrosis factor (TNF)-α are elevated in dorsal root ganglia in aged WT and eIF4E transgenic groups, despite faster resolution of acute inflammation and pain in the aged eIF4E transgenic animals. We propose that these cytokines are important in mediating the observed behavioral responses in the young and represent an alternate pathway in the development of age-associated inflammation and behavioral consequences. These findings demonstrate that eIF4E phosphorylation can be a key target for treating inflammatory pain in the aged.

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All data gathered and presented here as well as raw data will be made available for review upon request.

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Acknowledgments

The authors would like to thank Han Saim Jeong and Aspen L. Samuel for the technical assistance.

Funding

This research was funded by the National Institutes of Health/National Institute of Neurological Disorders and Stroke, grant number NS096030 (M.D.B.), the University of Texas System STARS program research support grant (M.D.B.), the American Pain Society Future Leaders Grant (M.D.B.), and a Rita Allen Foundation Grant (M.D.B.).

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Authors and Affiliations

  1. Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, Richardson, TX, 75080, USA

    Prapti H. Mody, Natalia L. Dos Santos, Luz R. Barron & Michael D. Burton

  2. Pain Neurobiology Research Group, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, Richardson, TX, 75080, USA

    Theodore J. Price

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  1. Prapti H. Mody
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  4. Theodore J. Price
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  5. Michael D. Burton
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Contributions

Conceptualization, N.L.S.; methodology, N.L.S.; analysis, N.L.S. and P.H.M.; data curation, N.L.S., L.B., and P.H.M.; writing manuscript and drawing figures, N.L.S., L.R.B., and P.H.M.; T.J.P. writing manuscript and collaborator; M.D.B participated and supervised in all aspects of the study conception to manuscript preparation.

Corresponding author

Correspondence to Michael D. Burton.

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Conflict of interest

The authors except T.J.P. declare no conflict of interest. T.J.P. is a cofounder of 4E Therapeutics, a company developing MNK inhibitors for neuropathic pain. 4E Therapeutics played no role in funding the study.

Ethics approval

All procedures were in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the University of Texas at Dallas Institutional Animal Care and Use Committee protocols 15-15 and 16-07.

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Mody, P.H., Dos Santos, N.L., Barron, L.R. et al. eIF4E phosphorylation modulates pain and neuroinflammation in the aged. GeroScience 42, 1663–1674 (2020). https://doi.org/10.1007/s11357-020-00220-1

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