TRPA1 insensitivity of human sural nerve axons after exposure to lidocaine

Abstract

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.

Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain

“…In the sciatic nerve, FKN-induced production of ROS from CX3CR1-expressing macrophages in the vicinity of sensory axons could result in a pronociceptive effect through the activation of TRPA1 receptors that are functionally located at axonal level (39)(40)(41). Thus, we demonstrated that 2 TRPA1 antagonists, AP-18 and A967079, repeatedly administered during the first VCR cycle, significantly prevented the development of VCR-induced allodynia by approximately 20% (Supplemental Figure 9).…”

“…Surprisingly, MO loses efficacy in human isolated sural nerves, but this is very likely due to nerve exposure to local anesthetic during surgery. Indeed, lidocaine desensitizes murine TRPA1 channel, thereby suggesting that this mechanism, in combination with sodium channel blockade, underlies lidocaine efficacy in treating neuropathic pain (39). This is a plausible suggestion, as TRPA1-immunoreactive fibers are expressed in human peripheral nerves (41).…”

Pain thresholds, supra‐threshold pain and lidocaine sensitivity in patients with erythromelalgia, including the I848Tmutation in NaV 1.7

“…A-delta fibres in the rat sciatic nerve had half maximum blocking concentration of lidocaine of 0.32 mmol/L which was much lower than for C-fibres (0.8 mmol/L) (Huang et al, 1997)possibly linked to Na V 1.6 expression in A-delta fibres compared to TTXr Na V 1.8 (Kistner et al, 2010) in Cfibres. Lidocaine may also mediate effects via other relevant membrane components, such as K + -channels (Brau et al, 1995;Nayak et al, 2009), Na + /K + pumps (Almotrefi et al, 1999;Zeng et al, 1999;Kutchai et al, 2000), Ca 2+ -channels (Guo et al, 1991), TRPA1 Docherty et al, 2013) and TRPV1 (Leffler et al, 2008). Lidocaine may also mediate effects via other relevant membrane components, such as K + -channels (Brau et al, 1995;Nayak et al, 2009), Na + /K + pumps (Almotrefi et al, 1999;Zeng et al, 1999;Kutchai et al, 2000), Ca 2+ -channels (Guo et al, 1991), TRPA1 Docherty et al, 2013) and TRPV1 (Leffler et al, 2008).…”

A Review of Intravenous Lidocaine Infusion Therapy for Paediatric Acute and Chronic Pain Management

“…This may reflect the prolonged analgesic effects sometimes seen that outlast the expected presence of lidocaine in the tissue [163].…”