Combined Nav1.7–Nav1.8 channel abrogation: Supralinear suppression of excitability in a subpopulation of peripheral sensory neurons

There is a pressing need for nonaddictive pain therapeutics. Despite the genetic validation of peripheral voltage-gated sodium (Nav) channels as targets for non-opioid pain therapy, isoform-selective inhibition of Nav1.7 and Nav1.8 has yielded limited efficacy in clinical studies, with Nav1.8 blockade providing statistically significant but only partial pain relief. This raises the question: if block of Nav1.8 relieves pain only partially, what is needed for better pain relief? In this study, we utilized dynamic clamp, which permits precisely calibrated functional addition or subtraction of the current from any given channel, to systematically interrogate the combinatorial landscape of multiplex abrogation of currents from Nav1.7 and Nav1.8, both major contributors to electrogenesis within dorsal root ganglion neurons. We demonstrate that partial, simultaneous attenuation of both conductances drives a supralinear increase in current threshold in many sensory neurons. Responses to Nav1.8 functional subtraction span a broad spectrum, whereas responses to Nav1.7 subtraction are comparatively uniform. Neurons with greater sensitivity to functional loss of Nav1.8 show greater suppression of excitability during combined Nav1.7-Nav1.8 attenuation, while weak Nav1.8 responders remain comparatively resistant. These findings identify electrogenic dependence on Nav1.8 as a major source of functional heterogeneity in sensory neurons and demonstrate that Nav1.7 acts cooperatively with Nav1.8 to shape the consequences of channel attenuation. Our results indicate that combined Nav1.7-Nav1.8 targeting should outperform isoform-selective block in suppressing firing in a subpopulation of pain-signaling neurons, while not producing universal suppression.