[8][9] Sodium voltage-gated channel alpha subunit 9 plays a critical role in the generation and conduction of action potentials and is thus important for electrical signaling by most excitable cells.

Stimulation of the nociceptor nerve endings produces "generator potentials", which are small changes in the voltage across the neuronal membranes.

In sensory neurons, multiple voltage-dependent sodium currents can be differentiated by their voltage dependence and by sensitivity to the voltage-gated sodium-channel blocker tetrodotoxin.

Stimulation of the nociceptor nerve endings produces "generator potentials", small changes in the voltage across the neuronal membranes.

Fluorogenic signaling probes and flow cytometry have been used to create laboratory cells that comprise heteromultimetic Nav1.7 including at least two of its accessory subunits.

[13] The critical role of Nav1.7 in nociception and pain was originally shown using Cre-Lox recombination tissue specific knockout mice.

Whilst Nav1.7 expressed in Nav1.8 negative DRG neurons is critical for normal responses to acute thermal pain assays.

Mutation in Nav1.7 may result in primary erythromelalgia (PE), an autosomal dominant, inherited disorder which is characterized by attacks or episodes of symmetrical burning pain of the feet, lower legs, and sometimes hands, elevated skin temperature of affected areas, and reddened extremities.

[18] In addition, in response to a slow, depolarizing stimulus, most mutant channels will generate a larger than normal sodium current.

Each of these alterations in activation and deactivation can contribute to the hyperexcitability of pain-signaling DRG neurons expressing these mutant channels, thus causing extreme sensitivity to pain (hyperalgesia).

[19] Local anesthetics such as lidocaine, but also the anticonvulsant phenytoin, mediate their analgesic effects by non-selectively blocking voltage-gated sodium channels.

[41] Development of the venom-derived peptide, JNJ63955 allowed for selective inhibition of Nav1.7 only while it was in the closed state, which produced results, in mice, much more similar to knock-out models.

[41] The proposed mechanism also suggests that the analgesic effects of Nav1.7 blockers may be greatly potentiated by the co-administration of exogenous opioids or enkephalinase inhibitors.

[41] Supporting this idea, a strong analgesic synergy between local anesthetics and topical opioids has already been observed in clinical research.