Modulation of human dorsal root ganglion neuron excitability by Nav1.7 inhibition

Researchers have investigated the impact of Nav1.7 inhibition on the excitability of human dorsal root ganglion neurons. Nav1.7 voltage-gated sodium channels are abundant in human primary pain-sensing neurons, or nociceptors, and selective Nav1.7 inhibitors have been explored as potential pain treatments, but clinical outcomes have been disappointing.

Suzetrigine, a selective Nav1.8 channel inhibitor, has, however, shown success in clinical trials. Given that nociceptors express both Nav1.7 and Nav1.8 channels, it is intriguing to compare the effects of Nav1.7 and Nav1.8 inhibitors on the excitability of human nociceptors. To establish a benchmark for comparison with suzetrigine, the research team studied the effects of a selective Nav1.7 inhibitor, AM-2099, on dissociated human dorsal root ganglion neurons at 37°C.

Inhibition of Nav1.7 channels using AM-2099 led to several changes in action potential generation and repetitive firing. Generally, the action potential threshold was significantly depolarized, the rheobase increased, the upstroke velocity decreased, the peak action potential became smaller, and the refractory period lengthened.

When compared to the effects of Nav1.8 inhibition, the Nav1.7 inhibition produced more substantial alterations in threshold and maximal upstroke velocity. Interestingly, the peak action potential was reduced similarly by both types of inhibition. While Nav1.7 inhibition did affect the excitability of human DRG neurons, most notably by increasing the threshold and refractory period, repetitive firing of the neurons in response to strong stimuli was only minimally affected.