Lidocaine reduces the transition to slow inactivation in Na(v)1.7 voltage-gated sodium channels

The primary use of local anaesthetics is to prevent or relieve pain by reversibly preventing action potential propagation through the inhibition of voltage-gated sodium channels. The tetrodotoxin-sensitive voltage-gated sodium channel subtype Na(v)1.7, abundantly expressed in pain-sensing neurons, plays a crucial role in perception and transmission of painful stimuli and in inherited chronic pain syndromes. Understanding the interaction of lidocaine with Na(v)1.7 channels could provide valuable insight into the drug's action in alleviating pain in distinct patient populations. The aim of this study was to determine how lidocaine interacts with multiple inactivated conformations of Na(v)1.7 channels.

We investigated the interactions of lidocaine with wild-type Na(v)1.7 channels and a paroxysmal extreme pain disorder mutation (I1461T) that destabilizes fast inactivation. Whole cell patch clamp recordings were used to examine the activity of channels expressed in human embryonic kidney 293 cells.

Depolarizing pulses that increased slow inactivation of Na(v)1.7 channels also reduced lidocaine inhibition. Lidocaine enhanced recovery of Na(v)1.7 channels from prolonged depolarizing pulses by decreasing slow inactivation. A paroxysmal extreme pain disorder mutation that destabilizes fast inactivation of Na(v)1.7 channels decreased lidocaine inhibition.

Lidocaine decreased the transition of Na(v)1.7 channels to the slow inactivated state. The fast inactivation gate (domain III-IV linker) is important for potentiating the interaction of lidocaine with the Na(v)1.7 channel.