背根神经节
伤害感受器
神经病理性疼痛
感觉神经元
电生理学
医学
药理学
感觉系统
神经科学
伤害
内科学
生物
受体
作者
Yan Li,Megan L. Uhelski,Robert Y. North,Juliet M. Mwirigi,Claudio E. Tatsui,Kathleen E. McDonough,Juan P. Cata,German Corrales,Gregory Dussor,Theodore J. Price,Patrick M. Dougherty
出处
期刊:Brain
[Oxford University Press]
日期:2024-07-24
卷期号:147 (9): 2991-2997
被引量:2
标识
DOI:10.1093/brain/awae178
摘要
Abstract 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.
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