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

Nav1.7 voltage-gated sodium channels are strongly expressed in human primary painsensing 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 Nav.7 inhibitor, AM-2099, on action potential generation and repetitive firing of dissociated human dorsal root ganglion 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 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.

Nav1.7 sodium channels are highly expressed in primary pain-sensing neurons and humans with null mutations in Nav1.7 channels have loss of pain sensation. However, unlike the Nav1.8 inhibitor suzetrigine, Nav1.7 inhibitors have so far not reached clinical use. We compared effects of Nav1.7 on electrical excitability of human dorsal root ganglion neurons with those of suzetrigine and found that while Nav1.7 inhibition affects spike threshold more than suzetrigine, there is little effect on repetitive firing with strong stimuli.