The excitability of sensory neurons depends on the expression of various voltage-gated Na+ channel isoforms. The tetrodotoxin-resistant (TTXr) Na+ channel Nav1.8 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 Nav1.8 heterologously expressed in ND7/23 cells in comparison with TTXs Na+ channels endogenously expressed in ND7/23 cells. TTXr Nav1.8 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 Nav1.8 channels. Use-dependent block by amitriptyline was similar in TTXs and Nav1.8 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 Nav1.8-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.
|Number of pages||11|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 2007|