Neuropathic pain is frequently associated with hyperexcitability of primary afferents, characterized by spontaneous impulses and repetitive firing. Electrophysiology and molecular biology reveal changes in dorsal root ganglion Na+ channels under conditions of neuropathic pain, but the manner by which these changes alter the physiology of sensory afferents remains unknown. Equally mysterious is the mechanism by which i.v. local anaesthetic-like Na+ channel blockers suppress neuropathic pain behaviour at concentrations well below those reported for channel inhibition. We have compared the anti-allodynic actions of i.v. lidocaine (L) and stereoisomers of mexiletine (R-M, S-M), in rats after spinal nerve ligation, with their ability: (1) to inhibit fast, tetrodotoxin-sensitive neuronal Na+ currents, elicited by brief (1 ms) pulses, at 10 Hz, from 'resting' potentials (-80, -60 mV) and (2) to suppress the seconds long plateau and the repetitive firing produced in axons by slowing of Na+ channel inactivation (e.g. using scorpion α-toxins). Both L and R-M at 5-10 μM relieved allodynia; S-M was ineffective. Na+ currents also were inhibited by M, with affinities that were increased by both repetitive 'firing' (KR,S = 5 μM) and depolarization of the 'resting' membrane (KR = 15 μM; KS = 30 μM). Stereopotency ratios depended on the manner in which different states of the channel were inducted. Both L and M shortened the action potential's 'plateau' in α-toxin treated axons, without reducing the spike, and suppressed repetitive firing with IC50s = 5 μM, and no stereoselectivity. These findings together demonstrate that Na+ channel blockers, at 'therapeutic' concentrations, can inhibit neuronal hyperexcitability.
|Number of pages||17|
|Journal||Novartis Foundation symposium|
|State||Published - 2002|