Prefrontal cortex pyramidal neurons express functional Nav1.8 tetrodotoxin‐resistant sodium currents

Abstract

There are two types of voltage-gated sodium channels: tetrodotoxin (TTX)-sensitive and TTX-resistant channels. TTX-sensitive sodium currents are widely present in both the central and peripheral nervous systems. 1 On the other hand, TTX-resistant sodium currents are extensively described in peripheral neurons, where they play an important role in nociception, including allodynia and hyperalgesia. [2][3][4][5][6][7][8][9][10] Neuronal TTX-resistant sodium currents are carried by two types of sodium channels, Nav1.8 and Nav1.9, which are localized in small diameter peripheral neurons. 9 In the sciatic nerve ligation model, upregulation of Nav1.8 along uninjured nerve fibres was observed, and its blockade with antisense oligodeoxynucleotides reversed neuropathic pain. 5 Moreover, pharmacological agents targeting Nav1.8 showed significant antinociception in animal models of neuropathic pain. 6,11

Evaluation of Nav1.8 as a therapeutic target for Pitt Hopkins Syndrome

“…SCN10a/Nav1.8 is a primarily peripherally expressed, TTX resistant, voltage-gated sodium channel (16), but its expression and function in the central nervous system is reported (6,17,18) and SCN10a variants are associated with epileptic disorders (19). In the peripheral nervous system, Nav1.8 is thought to play an important role in nociception (20)(21)(22)(23) and in dorsal root ganglion cells (DRGs) Nav1.8 is responsible for a substantial proportion of the inward current needed to generate an action potential (24).…”

“…Selective inhibitors of Na v 1.8 have been developed and have shown promise in rodent pain models as well as in early phase human trials. The selective Na v 1.8 inhibitor A-803467 has shown significant effects on the maximal amplitude and kinetic properties of the TTX-resistant sodium current in rats (17). A-803467, exhibited high affinity and selectivity for blocking human Na v 1.8 channels and effectively inhibited spontaneous and evoked DRG neuronal action potentials in vivo in rats.…”

Evaluation of Nav1.8 as a therapeutic target for Pitt Hopkins Syndrome

“…Selective inhibitors of Na v 1.8 have been developed and have shown promise in rodent pain models as well as in early phase human trials. The selective Na v 1.8 inhibitor A-803467 has shown significant effects on the maximal amplitude and kinetic properties of the TTX-resistant sodium current in rats [ 18 ]. A-803467, exhibited high affinity and selectivity for blocking human Na v 1.8 channels and effectively inhibited spontaneous and evoked DRG neuronal action potentials in an in vivo rat preparation.…”

“…SCN10A/NA V 1.8 FUNCTION AND PHARMACOLOGY SCN10a/Na v 1.8 is primarily a peripherally expressed, TTX resistant, voltage-gated sodium channel [17]. However, its expression and function in the central nervous system is reported [6,18,19] and SCN10a variants are associated with epileptic disorders [20]. In the peripheral nervous system, Na v 1.8 is thought to play an important role in nociception [21][22][23][24] and in dorsal root ganglion cells (DRGs) Na v 1.8 is responsible for a substantial proportion of the inward current needed to generate an action potential [25].…”