Propranolol modulation of tetrodotoxin-resistant Na⁺ channels in dural afferent neurons

Propranolol, a representative adrenergic β-receptor antagonist, is widely used to prevent migraine attacks. Although propranolol is well known to inhibit tetrodotoxin-resistant (TTX-R) Na⁺ channels in cardiac myocytes, it is unclear whether the drug modulates these channels expressed in dural afferent neurons. In this study, we examined the effects of propranolol on TTX-R Na⁺ channels in medium-sized dural afferent neurons identified by the fluorescent dye DiI. The TTX-R Na⁺ currents (I_Na) were recorded from acutely isolated DiI-positive neurons using a whole-cell patch clamp technique under voltage-clamp conditions. Propranolol inhibited the noninactivating steady-state component more potently than the peak component of transient TTX-R I_Na. Propranolol also potently inhibited the slow voltage ramp-induced TTX-R I_Na in a concentration-dependent manner, suggesting that it preferentially inhibited the noninactivating or persistent I_Na in DiI-positive neurons. Propranolol had little effect on voltage dependence, but it increased the extent of the use-dependent inhibition of TTX-R Na⁺ channels. Propranolol also accelerated the onset of inactivation and retarded recovery from inactivation in these channels. Under current-clamp conditions, propranolol decreased the number of action potentials elicited by depolarizing current stimuli. In conclusion, the propranolol-mediated preferential inhibition of persistent I_Na and modulation of the inactivation kinetics of TTX-R Na⁺ channels might represent additional mechanisms for migraine prophylaxis.