[8] Voltage-gated sodium channels are membrane protein complexes that play a fundamental role in the rising phase of the action potential in most excitable cells.

Following depolarization of the cell, voltage-gated sodium channels become inactivated through a change in conformation in which the 4th segments in each domain move into the pore region in response to the highly positive voltage expressed at the peak of the action potential.

[12][13] Though most sodium channels are blocked by tetrodotoxin, Nav1.9 is tetrodotoxin-resistant due to the presence of serine on an extracellular linker that plays a role in the selectivity of the pore for Na+.

The dorsal root ganglion of lumbar 4-5 of rats with bone cancer were shown to have up-regulation of Nav1.8 and Nav1.9 mRNA expression as well as an increase in total number of these alpha subunits.

These results suggest that tetrodotoxin-resistant voltage gated sodium channels are involved in the development and maintenance of bone cancer pain.

Expression of Nav1.9 in the afferent neurons of the dorsal root ganglion was found to be elevated as many as four weeks after the onset of the inflammatory pain.