Contribution of tetrodotoxin-resistant persistent Na(+) currents to the excitability of C-type dural afferent neurons in rats

BACKGROUND: Growing evidence supports the important role of persistent sodium currents (I(NaP)) in the neuronal excitability of various central neurons. However, the role of tetrodotoxin-resistant (TTX-R) Na(+) channel-mediated I(NaP) in the neuronal excitability of nociceptive neurons remains poorly understood. METHODS: We investigated the functional role of TTX-R I(NaP) in the excitability of C-type nociceptive dural afferent neurons, which was identified using a fluorescent dye, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchloride (DiI), and a whole-cell patch-clamp technique. RESULTS: TTX-R I(NaP) were found in most DiI-positive neurons, but their density was proportional to neuronal size. Although the voltage dependence of TTX-R Na(+) channels did not differ among DiI-positive neurons, the extent of the onset of slow inactivation, recovery from inactivation, and use-dependent inhibition of these channels was highly correlated with neuronal size and, to a great extent, the density of TTX-R I(NaP). In the presence of TTX, treatment with a specific I(NaP) inhibitor, riluzole, substantially decreased the number of action potentials generated by depolarizing current injection, suggesting that TTX-R I(NaP) are related to the excitability of dural afferent neurons. In animals treated chronically with inflammatory mediators, the density of TTX-R I(NaP) was significantly increased, and it was difficult to inactivate TTX-R Na(+) channels. CONCLUSIONS: TTX-R I(NaP) apparently contributes to the differential properties of TTX-R Na(+) channels and neuronal excitability. Consequently, the selective modulation of TTX-R I(NaP) could be, at least in part, a new approach for the treatment of migraine headaches. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10194-022-01443-7.