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Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block

: Brenneis, C.; Kistner, K.; Puopolo, M.; Jo, S.; Roberson, D.P.; Sisignano, M.; Segal, D.; Cobos, E.J.; Wainger, B.J.; Labocha, S.; Ferreirós, N.; Hehn, C. von; Tran, J.; Geisslinger, G.; Reeh, P.W.; Bean, B.P.; Woolf, C.J.


British journal of pharmacology 171 (2014), No.2, pp.438-451
ISSN: 0007-1188
ISSN: 1476-5381
Journal Article
Fraunhofer IME ()

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.
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.
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.
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.