Modulation of human dorsal root ganglion neuron excitability by Nav1.7 inhibition.
- 1Department of Neurobiology, Harvard Medical School, Boston, United States.
- 2AnaBios Corporation, San Diego, United States.
Abstract
Nav1.7 voltage-gated sodium channels are strongly expressed in human primary pain-sensing neurons (nociceptors), and selective Nav1.7 inhibitors have been developed as possible therapeutic agents for treating pain, so far with disappointing clinical results. In contrast, a selective Nav1.8 channel inhibitor (suzetrigine) has had successful clinical trials. Because nociceptors express both Nav1.7 and Nav1.8 channels, it is of interest to compare effects of Nav1.7 and Nav1.8 inhibitors on the excitability of human nociceptors. To compare with previous results with suzetrigine, we characterized the effects of a selective Nav1.7 inhibitor, AM-2099, on action potential generation and repetitive firing of dissociated human dorsal root ganglion (DRG) neurons, studied at 37°C. Inhibition of Nav1.7 channels by 600 nM AM-2099 generally produced a substantial depolarizing shift of action potential threshold, an increase in rheobase, a decrease in action potential upstroke velocity, decrease in action potential peak, and prolongation of the refractory period. Compared to inhibition of Nav1.8 channels, inhibition of Nav1.7 channels had larger effects on threshold and maximal upstroke velocity, while action potential peak was reduced similarly by both. Nav1.8 inhibition produced much more dramatic reduction of repetitive firing than Nav1.7 inhibition. The results show that although the excitability of human DRG neurons is affected by inhibition of Nav1.7 channels, most notably by an increase in threshold and increase in refractory period, repetitive firing of the neurons in response to strong stimuli is little affected.
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BibTeX
@article{fujita2026modulation,
title = {{Modulation of human dorsal root ganglion neuron excitability by Nav1.7 inhibition.}},
author = {Akie Fujita and Sooyeon Jo and Robert G Stewart and Tomás Osorno and Alyssa Ferraiuolo and Kevin Carlin and Bruce P Bean},
journal = {ELife},
year = {2026},
month = oct,
doi = {10.7554/elife.111490},
url = {https://europepmc.org/article/MED/42912422},
note = {CC BY},
}
RIS
TY - JOUR
TI - Modulation of human dorsal root ganglion neuron excitability by Nav1.7 inhibition.
AU - Akie Fujita
AU - Sooyeon Jo
AU - Robert G Stewart
AU - Tomás Osorno
AU - Alyssa Ferraiuolo
AU - Kevin Carlin
AU - Bruce P Bean
PY - 2026
DA - 2026/10/23
JO - ELife
DO - 10.7554/elife.111490
UR - https://europepmc.org/article/MED/42912422
AB - Nav1.7 voltage-gated sodium channels are strongly expressed in human primary pain-sensing neurons (nociceptors), and selective Nav1.7 inhibitors have been developed as possible therapeutic agents for treating pain, so far with disappointing clinical results. In contrast, a selective Nav1.8 channel inhibitor (suzetrigine) has had successful clinical trials. Because nociceptors express both Nav1.7 and Nav1.8 channels, it is of interest to compare effects of Nav1.7 and Nav1.8 inhibitors on the excitability of human nociceptors. To compare with previous results with suzetrigine, we characterized the effects of a selective Nav1.7 inhibitor, AM-2099, on action potential generation and repetitive firing of dissociated human dorsal root ganglion (DRG) neurons, studied at 37°C. Inhibition of Nav1.7 channels by 600 nM AM-2099 generally produced a substantial depolarizing shift of action potential threshold, an increase in rheobase, a decrease in action potential upstroke velocity, decrease in action potential peak, and prolongation of the refractory period. Compared to inhibition of Nav1.8 channels, inhibition of Nav1.7 channels had larger effects on threshold and maximal upstroke velocity, while action potential peak was reduced similarly by both. Nav1.8 inhibition produced much more dramatic reduction of repetitive firing than Nav1.7 inhibition. The results show that although the excitability of human DRG neurons is affected by inhibition of Nav1.7 channels, most notably by an increase in threshold and increase in refractory period, repetitive firing of the neurons in response to strong stimuli is little affected.
SN - 2050-084X
ER -