Activation of the integrated stress response in nociceptors drives methylglyoxal-induced pain. Issue 1 (January 2019)

• Record Type: Journal Article
• Authors: Barragán-Iglesias, Paulino; Kuhn, Jasper; Vidal-Cantú, Guadalupe C.; Salinas-Abarca, Ana Belen; Granados-Soto, Vinicio; Dussor, Gregory O.; Campbell, Zachary T.; Price, Theodore J.
• Is Part Of: Pain. Volume 160:Issue 1(2019)
• Publication Date: 2019-01
• Subjects: Integrated stress response -- Methylglyoxal -- ISRIB -- TRPA1 -- IB4 neurons; Pain -- Periodicals; Douleur -- Périodiques; Anesthésie -- Périodiques; Pain; Electronic journals; Periodicals; Electronic journals; 616.0472
• DOI: 10.1097/j.pain.0000000000001387
• Languages: English
• ISSNs: 0304-3959

Abstract

Abstract : 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. Abstract : Our work shows that methylglyoxal, a reactive metabolite associated with neuropathic pain, activates the integrated stress response in nociceptors to produce pain.