{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:48:14Z","timestamp":1791827294782,"version":"4.3.4"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2013,12,23]],"date-time":"2013-12-23T00:00:00Z","timestamp":1387756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2014,1]]},"abstract":"Background and Purpose<\/jats:title>Selective nociceptor fibre block is achieved by introducing the cell membrane impermeant sodium channel blocker lidocaine N\u2010ethyl bromide (QX<\/jats:styled-content>\u2010314) through transient receptor potential V<\/jats:styled-content>1 (TRPV1)<\/jats:styled-content> channels into nociceptors. We screened local anaesthetics for their capacity to activate TRP<\/jats:styled-content> channels, and characterized the nerve block obtained by combination with QX<\/jats:styled-content>\u2010314.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>We investigated TRP<\/jats:styled-content> channel activation in dorsal root ganglion (DRG<\/jats:styled-content>) neurons by calcium imaging and patch\u2010clamp recordings, and cellular QX<\/jats:styled-content>\u2010314 uptake by MS<\/jats:styled-content>. To characterize nerve block, compound action potential (CAP<\/jats:styled-content>) recordings from isolated nerves and behavioural responses were analysed.<\/jats:p><\/jats:sec>Key Results<\/jats:title>Of the 12 compounds tested, bupivacaine was the most potent activator of ruthenium red\u2010sensitive calcium entry in DRG<\/jats:styled-content> neurons and activated heterologously expressed TRPA1<\/jats:styled-content> channels. QX<\/jats:styled-content>\u2010314 permeated through TRPA1<\/jats:styled-content> channels and accumulated intracellularly after activation of these channels. Upon sciatic injections, QX<\/jats:styled-content>\u2010314 markedly prolonged bupivacaine's nociceptive block and also extended (to a lesser degree) its motor block. Bupivacaine's blockade of C<\/jats:styled-content>\u2010, but not A<\/jats:styled-content>\u2010fibre, CAPs<\/jats:styled-content> in sciatic nerves was extended by co\u2010application of QX<\/jats:styled-content>\u2010314. Surprisingly, however, this action was the same in wild\u2010type, TRPA1<\/jats:styled-content>\u2010knockout and TRPV1<\/jats:styled-content>\/TRPA1<\/jats:styled-content>\u2010double knockout mice, suggesting a TRP<\/jats:styled-content>\u2010channel independent entry pathway. Consistent with this, high doses of bupivacaine promoted a non\u2010selective, cellular uptake of QX<\/jats:styled-content>\u2010314.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>Bupivacaine, combined with QX<\/jats:styled-content>\u2010314, produced a long\u2010lasting sensory nerve block. This did not require QX<\/jats:styled-content>\u2010314 permeation through TRPA1<\/jats:styled-content>, although bupivacaine activated these channels. Regardless of entry pathway, the greatly extended duration of block produced by QX<\/jats:styled-content>\u2010314 and bupivacaine may be clinically useful.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12466","type":"journal-article","created":{"date-parts":[[2013,10,14]],"date-time":"2013-10-14T11:31:33Z","timestamp":1381750293000},"page":"438-451","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Bupivacaine\u2010induced cellular entry of QX<\/scp>\u2010314 and its contribution to differential nerve block"],"prefix":"10.1111","volume":"171","author":[{"given":"C","family":"Brenneis","sequence":"first","affiliation":[{"name":"F. M. 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