Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents.
BACKGROUND
Nociceptive-selective local anesthesia is produced by entry of the permanently charged lidocaine-derivative QX-314 into nociceptors when coadministered with capsaicin, a transient receptor potential vanilloid 1 (TRPV1) channel agonist. However, the pain evoked by capsaicin before establishment of the QX-314-mediated block would limit clinical utility. Because TRPV1 channels are also activated by lidocaine, the authors tested whether lidocaine can substitute for capsaicin to introduce QX-314 into nociceptors through TRPV1 channels and produce selective analgesia.


METHODS
Lidocaine (0.5% [17.5 mM], 1% [35 mM], and 2% [70 mM]) alone, QX-314 (0.2% [5.8 mM]) alone, and a combination of the two were injected subcutaneously and adjacent to the sciatic nerve in rats and mice. Mechanical and thermal responsiveness were measured, as was motor block.


RESULTS
Coapplication of 0.2% QX-314 with lidocaine prolonged the nociceptive block relative to lidocaine alone, an effect attenuated in TRPV1 knockout mice. The 0.2% QX-314 alone had no effect when injected intraplantary or perineurally, and it produced only weak short-lasting inhibition of the cutaneous trunci muscle reflex. Perisciatic nerve injection of lidocaine with QX-314 produced a differential nociceptive block much longer than the transient motor block, lasting 2 h (for 1% lidocaine) to 9 h (2% lidocaine). Triple application of lidocaine, QX-314, and capsaicin further increased the duration of the differential block.


CONCLUSIONS
Coapplication of lidocaine and its quaternary derivative QX-314 produces a long-lasting, predominantly nociceptor-selective block, likely by facilitating QX-314 entry through TRPV1 channels. Delivery of QX-314 into nociceptors by using lidocaine instead of capsaicin produces sustained regional analgesia without nocifensive behavior.
Binshtok
Alexander M
AM
Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Gerner
Peter
P
Oh
Seog Bae
SB
Puopolo
Michelino
M
Suzuki
Suzuko
S
Roberson
David P
DP
Herbert
Teri
T
Wang
Chi-Fei
CF
Kim
Donghoon
D
Chung
Gehoon
G
Mitani
Aya A
AA
Wang
Ging Kuo
GK
Bean
Bruce P
BP
Woolf
Clifford J
CJ
D000818:Animals; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D008012:Lidocaine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000008:administration & dosage*; D013997:Time Factors
D026941:Sodium Channel Blockers; C012647:QX-314; D008012:Lidocaine