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) in the neuronal excitability of various central neurons. However, the role of tetrodotoxin-resistant (TTX-R) Na channel-mediated I in the neuronal excitability of nociceptive neurons remains poorly understood.

Methods: We investigated the functional role of TTX-R I 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 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. In the presence of TTX, treatment with a specific I inhibitor, riluzole, substantially decreased the number of action potentials generated by depolarizing current injection, suggesting that TTX-R I are related to the excitability of dural afferent neurons. In animals treated chronically with inflammatory mediators, the density of TTX-R I was significantly increased, and it was difficult to inactivate TTX-R Na channels.

Conclusions: TTX-R I apparently contributes to the differential properties of TTX-R Na channels and neuronal excitability. Consequently, the selective modulation of TTX-R I could be, at least in part, a new approach for the treatment of migraine headaches.