The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons.
Local anesthetics (LAs) block the generation and propagation of action potentials by interacting with specific sites of voltage-gated Na(+) channels. LAs can also excite sensory neurons and be neurotoxic through mechanisms that are as yet undefined. Nonspecific cation channels of the transient receptor potential (TRP) channel family that are predominantly expressed by nociceptive sensory neurons render these neurons sensitive to a variety of insults. Here we demonstrated that the LA lidocaine activated TRP channel family receptors TRPV1 and, to a lesser extent, TRPA1 in rodent dorsal root ganglion sensory neurons as well as in HEK293t cells expressing TRPV1 or TRPA1. Lidocaine also induced a TRPV1-dependent release of calcitonin gene-related peptide (CGRP) from isolated skin and peripheral nerve. Lidocaine sensitivity of TRPV1 required segments of the putative vanilloid-binding domain within and adjacent to transmembrane domain 3, was diminished under phosphatidylinositol 4,5-bisphosphate depletion, and was abrogated by a point mutation at residue R701 in the proximal C-terminal TRP domain. These data identify TRPV1 and TRPA1 as putative key elements of LA-induced nociceptor excitation. This effect is sufficient to release CGRP, a key component of neurogenic inflammation, and warrants investigation into the role of TRPV1 and TRPA1 in LA-induced neurotoxicity.
Leffler
Andreas
A
Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
Fischer
Michael J
MJ
Rehner
Dietlinde
D
Kienel
Stephanie
S
Kistner
Katrin
K
Sauer
Susanne K
SK
Gavva
Narender R
NR
Reeh
Peter W
PW
Nau
Carla
C
D000779:Anesthetics, Local / Q000633:toxicity*; D000818:Animals; D017487:Ankyrins; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D005071:Evoked Potentials / Q000187:drug effects; D006801:Humans; D008012:Lidocaine / Q000633:toxicity*; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D018689:Sensory System Agents / Q000494:pharmacology; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
D000779:Anesthetics, Local; D017487:Ankyrins; D015220:Calcium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D011994:Recombinant Proteins; D018689:Sensory System Agents; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C480976:Trpa1 protein, rat; C493922:Trpv1 protein, rat; D008012:Lidocaine; D011493:Protein Kinase C; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin