Back to Search
Start Over
Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2014 Jan; Vol. 171 (2), pp. 438-51. - Publication Year :
- 2014
-
Abstract
- Background and Purpose: Selective nociceptor fibre block is achieved by introducing the cell membrane impermeant sodium channel blocker lidocaine N-ethyl bromide (QX-314) through transient receptor potential V1 (TRPV1) channels into nociceptors. We screened local anaesthetics for their capacity to activate TRP channels, and characterized the nerve block obtained by combination with QX-314.<br />Experimental Approach: We investigated TRP channel activation in dorsal root ganglion (DRG) neurons by calcium imaging and patch-clamp recordings, and cellular QX-314 uptake by MS. To characterize nerve block, compound action potential (CAP) recordings from isolated nerves and behavioural responses were analysed.<br />Key Results: Of the 12 compounds tested, bupivacaine was the most potent activator of ruthenium red-sensitive calcium entry in DRG neurons and activated heterologously expressed TRPA1 channels. QX-314 permeated through TRPA1 channels and accumulated intracellularly after activation of these channels. Upon sciatic injections, QX-314 markedly prolonged bupivacaine's nociceptive block and also extended (to a lesser degree) its motor block. Bupivacaine's blockade of C-, but not A-fibre, CAPs in sciatic nerves was extended by co-application of QX-314. Surprisingly, however, this action was the same in wild-type, TRPA1-knockout and TRPV1/TRPA1-double knockout mice, suggesting a TRP-channel independent entry pathway. Consistent with this, high doses of bupivacaine promoted a non-selective, cellular uptake of QX-314.<br />Conclusions and Implications: Bupivacaine, combined with QX-314, produced a long-lasting sensory nerve block. This did not require QX-314 permeation through TRPA1, although bupivacaine activated these channels. Regardless of entry pathway, the greatly extended duration of block produced by QX-314 and bupivacaine may be clinically useful.<br /> (© 2013 The British Pharmacological Society.)
- Subjects :
- Anesthetics, Local administration & dosage
Animals
Behavior, Animal drug effects
Bupivacaine administration & dosage
Calcium metabolism
Cell Line
Foot Injuries
Ganglia, Spinal drug effects
Ganglia, Spinal metabolism
Injections
Lidocaine metabolism
Male
Mice, Knockout
Patch-Clamp Techniques
Peripheral Nerves drug effects
Primary Cell Culture
Rats
Rats, Sprague-Dawley
Sciatic Nerve drug effects
TRPA1 Cation Channel
Transient Receptor Potential Channels genetics
Transient Receptor Potential Channels metabolism
Anesthetics, Local pharmacology
Bupivacaine pharmacology
Lidocaine analogs & derivatives
Nerve Block
Sodium Channel Blockers metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 171
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24117225
- Full Text :
- https://doi.org/10.1111/bph.12466