Use-dependent block by lidocaine but not amitriptyline is more pronounced in tetrodotoxin (TTX)-resistant Na(v)1.8 than in TTX-sensitive Na+ channels

The excitability of sensory neurons depends on the expression of various voltage- gated Na+ channel isoforms. The tetrodotoxinresistant ( TTXr) Na+ channel Na v 1.8 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 v 1.8 heterologously expressed in ND7/ 23 cells in comparison with TTXs Na+ channels endogenously expressed in ND7/ 23 cells. TTXr Na v 1.8 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 v 1.8 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 v 1.8 channels. Use- dependent block by amitriptyline was similar in TTXs and Na v 1.8 channels. Surprisingly, use-dependent block by lidocaine was more pronounced in Na v 1.8 than in TTXs channels. This result was confirmed in dorsal root ganglion neurons and is associated with the greater tendency of Na v 1.8 to enter a slow inactivated state. Our data suggest that lidocaine could selectively block Na v 1.8- 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.