ArticleThe Journal of general physiology2025
Differential state-dependent Nav1.8 inhibition by suzetrigine, LTGO-33, and A-887826.
Article in The Journal of general physiology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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The trial behind it
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Who cites it
17 citing papers in PubMed.
- A designer saxitoxin-engineered sodium channel pair as a general tool for subtype-selective inhibition.Cell chemical biology · 2026Article
- Functional role of Nav1.8 channels in action potentials of mouse CGRP-lineage dorsal root ganglion neurons.The Journal of physiology · 2026Article
- Discovery and Optimization of Potent and Subtype-Selective Urea-Derived NaACS medicinal chemistry letters · 2026Article
- The Excelsatoxin A-Receptor TMEM233 Modulates Nav1.8.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Sodium Channel Inhibitors in Clinical Development for Pain Management: A Focused Review.CNS drugs · 2026Review
- Exceptionally selective voltage-sensor trapping of NaScientific reports · 2026Article
- Suzetrigine, a NaMolecules (Basel, Switzerland) · 2026Review
- From ion channel biology to clinical practice: suzetrigine as a precision analgesic.Frontiers in medicine · 2026Review
- A chemogenetic ligand-receptor pair for voltage-gated sodium channel subtype-selective inhibition.bioRxiv : the preprint server for biology · 2025Article
- Targeting sodium channels - challenges for acute pain and the leap to chronic pain.Nature reviews. Neurology · 2025Review
- Nav1.8: Intrinsic limits on the functional effect of abrogation in DRG neurons.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Suzetrigine: A Novel Non-Opioid Analgesic for Acute Pain Management-A Review.Drugs and drug candidates · 2025Article
- Sensory neuron sodium channels as pain targets; from cocaine to Journavx (VX-548, suzetrigine).The Journal of general physiology · 2025Review
- Modulation of human dorsal root ganglion neuron firing by the Nav1.8 inhibitor suzetrigine.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Voltage-Gated Ion Channels in Neuropathic Pain Signaling.Life (Basel, Switzerland) · 2025Review
- Nav1.8 and Chronic Pain: From Laboratory Animals to Clinical Patients.Biomolecules · 2025Review
- Biophysical dissection of nociceptor hyperexcitability caused by a Nav1.8 gain-of-function mutation linked to severe pain.Neurobiology of pain (Cambridge, Mass.)Article
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
Nav1.8 sodium channels are expressed in pain-sensing neurons, and some Nav1.8 inhibitors significantly reduce pain in clinical trials. Several Nav1.8 inhibitors have an unusual state dependence whereby inhibition is relieved by depolarization. We compared the state-dependent action of several Nav1.8 channel inhibitors to test whether inhibition is relieved during action potential (AP) firing under physiological conditions to produce "reverse use dependence." A-887826 inhibition was substantially relieved by AP waveforms applied at 20 Hz at 37°C. In contrast, there was no relief during AP trains with suzetrigine (VX-548) or LTGO-33, even though inhibition could be effectively removed by long, strong depolarizations. These differences were explained by differences in the voltage dependence and kinetics with which the compounds dissociate from depolarized channels and rebind to resting state channels. Suzetrigine required the strongest depolarizations for relief (midpoint +33 mV) and relief was slow (tau >300 ms at +20 mV), so almost no relief occurred during an AP waveform. Relief from A-887826 required weaker depolarizations (midpoint +13 mV) and was much faster, so some relief occurred during each AP waveform and accumulated during 20-Hz trains. LTGO-33 required the weakest depolarizations for relief (midpoint -11 mV) and relief was even faster than for A-887826, but reinhibition between AP waveforms was far faster than for A-887826, so that relief did not accumulate during AP trains at 20 Hz. The results show that, unlike A-887826, there is no use-dependent relief of inhibition by suzetrigine or LTGO-33 with physiological voltage waveforms at physiological temperatures, but each for different reasons.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.