Received for publication June 7, 2006.
Revised August 22, 2006.
Accepted for publication September 26, 2006.

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

Abstract

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 electro-responsiveness 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 TTX-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 to 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 DRG 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.

Key words: DRG neurons, local anesthetic, pain management, patch clamp, slow inactivation, sodium channel

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