Tomivosertib reduces ectopic activity in dorsal root ganglion neurons from patients with radiculopathy.

Autor:	Li Y; Department of Anesthesia and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Uhelski ML; Department of Anesthesia and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., North RY; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Mwirigi JM; School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.; Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, TX 75080, USA., Tatsui CE; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., McDonough KE; Department of Anesthesia and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Cata JP; Department of Anesthesiology & Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Corrales G; Department of Anesthesiology & Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Dussor G; School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.; Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, TX 75080, USA., Price TJ; School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.; Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, TX 75080, USA., Dougherty PM; Department of Anesthesia and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Sep 03; Vol. 147 (9), pp. 2991-2997.
DOI:	10.1093/brain/awae178
Abstrakt:	Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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