Activation of the integrated stress response in nociceptors drives methylglyoxal-induced pain
| Autor: | Guadalupe C. Vidal-Cantú, Vinicio Granados-Soto, Gregory Dussor, Theodore J. Price, Ana Belen Salinas-Abarca, Jasper L. Kuhn, Paulino Barragán-Iglesias, Zachary T. Campbell |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Pain Threshold Pain Mice Transgenic Pharmacology Article Diabetes Mellitus Experimental 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Dorsal root ganglion 030202 anesthesiology Stress Physiological Diabetes mellitus Ganglia Spinal Lectins Oximes medicine Integrated stress response Animals Phosphorylation Heat-Shock Proteins Mice Inbred ICR business.industry Methylglyoxal Nociceptors Analgesics Non-Narcotic medicine.disease Pyruvaldehyde ISRIB DNA-Binding Proteins Mice Inbred C57BL Disease Models Animal Anesthesiology and Pain Medicine medicine.anatomical_structure Neurology Mechanism of action chemistry Neuropathic pain Nociceptor Neurology (clinical) medicine.symptom business 030217 neurology & neurosurgery Signal Transduction Transcription Factors |
| Popis: | Methylglyoxal (MGO) is a reactive glycolytic metabolite associated with painful diabetic neuropathy at plasma concentration is 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. |
| Databáze: | OpenAIRE |
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