Suzetrigine (VX-548) exhibits activity-dependent effects on human dorsal root ganglion neurons with differential pain etiology
Abstract
Abstract Non-selective antagonists of voltage-gated sodium channels (VGSCs) provide effective local analgesia, but systemic administration is fraught with unwanted cardiovascular and central nervous system toxicity. The development of antagonists targeting VGSCs preferentially expressed in peripheral neurons, such as Na V 1.7, 1.8, and 1.9, could mitigate these risks. One such new small molecule that selectively inhibits Na V 1.8, is orally bioavailable, and has recent FDA approval for the treatment of acute pain is suzetrigine (VX-548). Here we tested the effects of this agent on human dorsal root ganglion (hDRG) neurons obtained from either patients undergoing surgical thoracic vertebrectomy or from organ donors in parallel electrophysiology studies across 2 laboratories. Bath application of 10 nM suzetrigine abolished spontaneous discharges previously shown to be associated with on-going neuropathic pain within minutes. In contrast, suppression of discharges evoked by intracellular current injection required more prolonged application times. These results suggest that suzetrigine will likely show efficacy versus spontaneous pain but may have less robust effects on evoked or breakthrough pain.
Read the paper
Related studies
- Noninvasive and Point-of-Care Surface-Enhanced Raman Scattering (SERS)-Based Breathalyzer for Mass Screening of Coronavirus Disease 2019 (COVID-19) under 5 min
- De Novo Transcriptome Analysis and Detection of Antimicrobial Peptides of the American Cockroach Periplaneta americana (Linnaeus)
- Molecular Characterization and Expression Profiling of Tomato GRF Transcription Factor Family Genes in Response to Abiotic Stresses and Phytohormones
- Assembly of Tight Junction Strands: Claudin-10b and Claudin-3 Form Homo Tetrameric Building Blocks that Polymerise in a Channel-Independent Manner
- Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease‐associated variants, common sequence variants, and results from newborn screening
- Machine Learning-Based SERS Chemical Space for Two-Way Prediction of Structures and Spectra of Untrained Molecules
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.