Binshtok AM et al. (2007) Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 449: 607–610

Local anesthetics such as lidocaine block pain effectively, but they also impair motor and autonomic functions by indiscriminately blocking sodium channels in all neurons. Binshtok et al. theorized that it could be possible to exploit the transient receptor potential vanilloid type 1 (TRPV1) channel, which is sensitive to noxious heat and capsaicin, to selectively target primary sensory nociceptor neurons and thereby produce a pain-specific local anesthetic.

Electrophysiological studies in cultured adult rat dorsal root ganglion neurons demonstrated that application of extracellular QX-314—a positively charged, membrane-impermeable lidocaine derivative—had no effect on sodium channel currents when applied alone, but that when co-applied with capsaicin it produced 98±0.4% inhibition of excitability, an effect limited to neurons expressing TRPV1. In vivo, intraplantar injection of QX-314 followed by capsaicin anesthetized adult rats to mechanical and thermal noxious stimuli for around 3h. Injection adjacent to the sciatic nerve with QX-314 followed 10min later by capsaicin produced a local anesthesia to noxious heat and mechanical stimuli applied to the lower limbs, without the motor deficit produced by similar injection with lidocaine alone. The QX-314+capsaicin-injected animals showed no response to a mechanical stimulus of 57g, whereas the threshold before sciatic injection was 15.23.4g (P<0.01); similarly, thermal response latency increased from 14.9±0.4s before injection, to 22.3±2.3s after injection (P<0.05).

The results of this study suggest that delivery of a lidocaine derivative together with a TRPV1 receptor agonist selectively inhibits nociceptors to produce a long-lasting decrease in pain without the loss of motor or autonomic responses.