Nav1.8

Nav1.8, also known as SCN10A, is a voltage-gated sodium channel alpha subunit isoform predominantly expressed in dorsal root ganglion (DRG) neurons and sympathetic ganglion neurons. These neurons are involved in nociception, the sensory process of pain. Nav1.8 plays a crucial role in the generation and propagation of action potentials in these neurons, particularly those that detect noxious stimuli, such as heat, pressure, and inflammatory mediators.

Nav1.8 is characterized by its slow inactivation kinetics, relatively depolarized voltage dependence of activation, and resistance to tetrodotoxin (TTX), a potent neurotoxin that blocks most other voltage-gated sodium channels. This resistance to TTX makes Nav1.8 a key contributor to the TTX-resistant sodium current observed in many nociceptive neurons.

Genetic studies have linked mutations in the SCN10A gene, which encodes Nav1.8, to a range of pain disorders, including inherited erythromelalgia (IEM), small fiber neuropathy (SFN), and painful channelopathies. These mutations can either increase or decrease the excitability of nociceptive neurons, leading to either gain-of-function or loss-of-function phenotypes, respectively. Gain-of-function mutations typically result in increased pain sensitivity, while loss-of-function mutations can result in reduced pain sensitivity or even congenital insensitivity to pain.

The unique biophysical properties and specific expression pattern of Nav1.8 make it a promising therapeutic target for the development of novel analgesics. Research efforts are focused on developing selective Nav1.8 inhibitors that can selectively block the activity of this channel in nociceptive neurons, thereby reducing pain without affecting other sodium channels in the nervous system.