*5.1. Voltage-Gated Sodium Channels*

VGSCs are responsible for action potential generation and excitability of the cell membrane. Nine different VGSC isoforms have been discovered in the mammalian nervous system, with NaV1.6 and NaV1.7 being the most abundant in the peripheral nervous system [150] and nociceptive sensory neurons [151], respectively. Immunohistochemical analysis of pulp tissue taken from pulpitis patients revealed expression of NaV1.7 and NaV1.8 with greater immunoreactivity in the pulp from patients with painful pulpitis [152–154]. Closer investigation of tooth pulp from pulpitis patients showed an increased expression of NaV1.7 in the nerve bundles at intact and demyelinating nodes of Ranvier compared with healthy tooth pulp [155], while no significant difference for NaV1.6 expression was observed [156]; together, this suggests that NaV1.7 might play a role in inflammatory tooth pain.

Since expression of VGSCs is an important property of excitable cells, the demonstration of NaV1.6 expression in non-neuronal pulpal cells, such as pulpal immune cells, dendritic pulpal cells, and odontoblasts [29], has gathered a robust interest. In addition, electrophysiology, immunohistochemistry, RT-PCR, and in situ hybridization of odontoblasts differentiated from human dental pulp explants has revealed the expression and functionality of NaV1.1, NaV1.2, and NaV1.3 [28]. Interestingly, patch-clamp recording of the cultured human tooth pulp cells revealed rapidly inactivating TTX-sensitive Na<sup>+</sup> currents and membrane properties similar to neuronal satellite cells but not to odontoblasts [157]. The molecular and cellular identity of such pulpal cells is still unknown, and whether odontoblasts or other pulpal cells are indeed excitable and, if so, what their function would be, is unclear.

NaV1.9 is the VGSC most recently identified [158]. NaV1.9 is preferentially expressed in small-diameter DRG neurons, TG neurons, and myenteric neurons [159–162] NaV1.9 is activated at voltages near the resting membrane potential and generates a relatively persistent current [159]. NaV1.9 channels may also have a role in inflammatory pain, but not in neuropathic pain [158,163]. In addition, an investigation of NaV1.9 in rats revealed the innervation of NaV1.9-IR fibers in lip skin and in the tooth pulp of non-painful teeth, suggesting a role of this VGSC isoform in orofacial pain [164]. Recently, a study found that NaV1.9 was increased in the axons of symptomatic pulpitis of permanent painful human teeth compared to the tooth pulp of permanent non-painful teeth (Figure 4) [165].
