Tomivosertib Reduces Ectopic Activity in Dorsal Root Ganglion Neurons From Patients With Radiculopathy

Authors

Yan Li
Megan L Uhelski
Robert Y North
Juliet M Mwirigi
Claudio E Tatsui
Kathleen E McDonough
Juan P Cata
German Corrales
Greg Dussor
Theodore J Price
Patrick M Dougherty

Language

English

Publication Date

9-3-2024

Journal

Brain

DOI

10.1093/brain/awae178

PMID

39046204

PMCID

PMC11370786

PubMedCentral® Posted Date

7-24-2024

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Ganglia, Spinal, Humans, Male, Action Potentials, Radiculopathy, Cells, Cultured, Middle Aged, Female, Aged, Neuralgia, Nociceptors, Sulfones, Sensory Receptor Cells, ion channels, eFT508, human DRG excitability, MNK

Published Open-Access

yes

Recommended Citation

Li, Yan; Uhelski, Megan L; North, Robert Y; et al., "Tomivosertib Reduces Ectopic Activity in Dorsal Root Ganglion Neurons From Patients With Radiculopathy" (2024). Faculty, Staff and Student Publications. 5605.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5605