Action potential is initiated by voltage-gated sodium channels. Alterations in channel properties can contribute to inflammatory and neuropathic pain. Voltage-gated sodium channels are transmembrane proteins that are selective for sodium ions and are regulated by voltage across the membrane. Nine different subtypes have been identified (Nav1.1–Nav1.9). Dorsal root ganglion expresses a variety of sodium channels that may be pufferfish toxin tetrodotoxin resistant or sensitive. Their distribution is as follows:

Nav1.7 and Nav1.8 are predominantly seen in the peripheral nervous system. Nav1.8 and Nav1.9 are present in small-diameter neurons that are related to nociception. Nav1.3 concentration increases after nerve injury. A decrease in levels of Nav1.8 mRNA decreases pain sensation, and alteration of its properties play a role in the onset of neuropathic pain. Lack of Nav1.7 and Nav1.8 can lead to expression of neuropathic pain.

Nav1.7 mutation can lead to two pain syndromes – inherited erythromelalgia and paroxysmal extreme pain disorder.

Inherited erythromelalgia: a severe burning sensation is seen especially in the hands and feet. Increased excitability of sensory neurons is seen.