Activation of the integrated stress response in nociceptors drives methylglyoxal-induced pain.

Pain
Paulino Barragán-IglesiasTheodore J Price

Abstract

Methylglyoxal (MGO) is a reactive glycolytic metabolite associated with painful diabetic neuropathy at plasma concentrations between 500 nM and 5 μM. The mechanisms through which MGO causes neuropathic pain at these pathological concentrations are not known. Because MGO has been linked to diabetic neuropathic pain, which is prevalent and poorly treated, insight into this unsolved biomedical problem could lead to much needed therapeutics. Our experiments provide compelling evidence that ∼1-μM concentrations of MGO activate the integrated stress response (ISR) in IB4-positive nociceptors in the dorsal root ganglion (DRG) of mice in vivo and in vitro. Blocking the integrated stress response with a specific inhibitor (ISRIB) strongly attenuates and reverses MGO-evoked pain. Moreover, ISRIB reduces neuropathic pain induced by diabetes in both mice and rats. Our work elucidates the mechanism of action of MGO in the production of pain at pathophysiologically relevant concentrations and suggests a new pharmacological avenue for the treatment of diabetic and other types of MGO-driven neuropathic pain.

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Citations

Jul 18, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Muhammad Saad YousufBradley J Kerr
Aug 14, 2020·Molecular Pain·Muhammad Saad YousufBradley J Kerr
May 16, 2019·Wiley Interdisciplinary Reviews. RNA·June Bryan I de la PeñaZachary T Campbell
Nov 30, 2019·Brain Research Bulletin·Wen-Jun ZhangZeng-Xu Liu
Nov 19, 2020·Pharmacological Reviews·Muhammad Saad YousufTheodore J Price
Nov 13, 2020·Frontiers in Pharmacology·Guadalupe Del Carmen Baeza-FloresVinicio Granados-Soto
May 12, 2021·Proceedings of the National Academy of Sciences of the United States of America·Satoshi WatanabeAlexander V Misharin

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