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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Voltage-Gated Na Channels|
March 26 2025
Differential state-dependent Nav1.8 inhibition by suzetrigine, LTGO-33, and A-887826
Sooyeon Jo
,
Sooyeon Jo
*
(Conceptualization, Investigation, Methodology, Validation, Visualization, Writing - review & editing)
1Department of Neurobiology,
Harvard Medical School
, Boston, MA, USA
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Akie Fujita
,
Akie Fujita
*
(Conceptualization, Investigation, Methodology, Validation, Visualization, Writing - review & editing)
1Department of Neurobiology,
Harvard Medical School
, Boston, MA, USA
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Tomás Osorno
,
Tomás Osorno
*
(Conceptualization, Investigation, Methodology, Validation, Visualization, Writing - review & editing)
1Department of Neurobiology,
Harvard Medical School
, Boston, MA, USA
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Robert G. Stewart
,
Robert G. Stewart
*
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing)
1Department of Neurobiology,
Harvard Medical School
, Boston, MA, USA
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Patric M. Vaelli
,
Patric M. Vaelli
(Conceptualization, Methodology)
1Department of Neurobiology,
Harvard Medical School
, Boston, MA, USA
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Bruce P. Bean
(Conceptualization, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Visualization, Writing - original draft, Writing - review & editing)
1Department of Neurobiology,
Harvard Medical School
, Boston, MA, USA
Correspondence to Bruce P. Bean: [email protected]
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Sooyeon Jo
Conceptualization, Investigation, Methodology, Validation, Visualization, Writing - review & editing
*
1Department of Neurobiology,
Harvard Medical School
, Boston, MA, USA
Akie Fujita
Conceptualization, Investigation, Methodology, Validation, Visualization, Writing - review & editing
*
1Department of Neurobiology,
Harvard Medical School
, Boston, MA, USA
Tomás Osorno
Conceptualization, Investigation, Methodology, Validation, Visualization, Writing - review & editing
*
1Department of Neurobiology,
Harvard Medical School
, Boston, MA, USA
Robert G. Stewart
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing
*
1Department of Neurobiology,
Harvard Medical School
, Boston, MA, USA
Patric M. Vaelli
Conceptualization, Methodology
1Department of Neurobiology,
Harvard Medical School
, Boston, MA, USA
Correspondence to Bruce P. Bean: [email protected]
*
S. Jo, A. Fujita, T. Osorno, and R.G. Stewart contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
This work is part of a special issue on Voltage-Gated Sodium (Nav) Channels.
Received:
October 29 2024
Revision Received:
February 18 2025
Accepted:
March 09 2025
Online ISSN: 1540-7748
Print ISSN: 0022-1295
Funding
Funder(s):
National Institutes of Health
- Award Id(s): R35-NS127216
© 2025 Jo et al.
2025
Jo et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Gen Physiol (2025) 157 (4): e202413719.
Article history
Received:
October 29 2024
Revision Received:
February 18 2025
Accepted:
March 09 2025
Citation
Sooyeon Jo, Akie Fujita, Tomás Osorno, Robert G. Stewart, Patric M. Vaelli, Bruce P. Bean; Differential state-dependent Nav1.8 inhibition by suzetrigine, LTGO-33, and A-887826. J Gen Physiol 7 July 2025; 157 (4): e202413719. doi: https://doi.org/10.1085/jgp.202413719
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