Use-dependent block by lidocaine but not amitriptyline is more pronounced in tetrodotoxin (TTX)-resistant Na_v1.8 than in TTX-sensitive Na ⁺ channels

The excitability of sensory neurons depends on the expression of various voltage-gated Na⁺ channel isoforms. The tetrodotoxin-resistant (TTXr) Na⁺ channel Na_v1.8 accounts for the electroresponsiveness of nociceptive neurons and contributes to inflammatory and neuropathic pain. Na⁺ channel blockers are clinically employed for chronic pain management, but side effects limit their use. There is conflicting information whether their potency to block tetrodotoxin-sensitive (TTXs) and TTXr Na ⁺ channels differs. We analyzed the action of lidocaine and amitriptyline on TTXr Na_v1.8 heterologously expressed in ND7/23 cells in comparison with TTXs Na⁺ channels endogenously expressed in ND7/23 cells. TTXr Na_v1.8 and TTXs currents were investigated under whole-cell voltage-clamp. At a holding potential of -80 mV, lidocaine was 5-fold and amitriptyline 8-fold more potent to tonically block TTXs than Na _v1.8 currents. This was due to a higher percentage of TTXs channels residing in the inactivated, high-affinity state at this potential. Tonic block of either resting or inactivated channels by lidocaine or amitriptyline revealed little differences between TTXs and Na_v1.8 channels. Use-dependent block by amitriptyline was similar in TTXs and Na_v1.8 channels. Surprisingly, use-dependent block by lidocaine was more pronounced in Na _v1.8 than in TTXs channels. This result was confirmed in dorsal root ganglion neurons and is associated with the greater tendency of Na _v1.8 to enter a slow inactivated state. Our data suggest that lidocaine could selectively block Na_v1.8-mediated action potential firing. It is conceivable that the expression pattern of Na⁺ channels in sensory neurons might influence the efficiency of Na⁺ channel blockers used for chronic pain management.