TRPA1 insensitivity of human sural nerve axons after exposure to lidocaine

TRPA1 is an ion channel of the TRP family that is expressed in some sensory neurons. TRPA1 activity provokes sensory symptoms of peripheral neuropathy, such as pain and paraesthesia. We have used a grease gap method to record axonal membrane potential and evoked compound action potentials (ECAPs) in vitro from human sural nerves and studied the effects of mustard oil (MO), a selective activator of TRPA1. Surprisingly, we failed to demonstrate any depolarizing response to MO (50, 250 μM) in any human sural nerves. There was no effect of MO on the A wave of the ECAP, but the C wave was reduced at 250 μM. In rat saphenous nerve fibres MO (50, 250 μM) depolarized axons and reduced the C wave of the ECAP but had no effect on the A wave. By contrast, both human and rat nerves were depolarized by capsaicin (0.5 to 5 μM) or nicotine (50 to 200 μM). Capsaicin caused a profound reduction in C fibre conduction in both species but had no effect on the amplitude of the A component. Lidocaine (30 mM) depolarized rat saphenous nerves acutely, and when rat nerves were pretreated with 30 mM lidocaine to mimic the exposure of human nerves to local anaesthetic during surgery, the effects of MO were abolished whilst the effects of capsaicin were unchanged. This study demonstrates that the local anaesthetic lidocaine desensitizes TRPA1 ion channels and indicates that it may have additional mechanisms for treating neuropathic pain that endure beyond simple sodium channel blockade.