title: Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents.
abstract: 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.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Binshtok
authors.forename: Peter
authors.initials: P
authors.lastname: Gerner
authors.forename: Seog Bae
authors.initials: SB
authors.lastname: Oh
authors.forename: Michelino
authors.initials: M
authors.lastname: Puopolo
authors.forename: Suzuko
authors.initials: S
authors.lastname: Suzuki
authors.forename: David P
authors.initials: DP
authors.lastname: Roberson
authors.forename: Teri
authors.initials: T
authors.lastname: Herbert
authors.forename: Chi-Fei
authors.initials: CF
authors.lastname: Wang
authors.forename: Donghoon
authors.initials: D
authors.lastname: Kim
authors.forename: Gehoon
authors.initials: G
authors.lastname: Chung
authors.forename: Aya A
authors.initials: AA
authors.lastname: Mitani
authors.forename: Ging Kuo
authors.initials: GK
authors.lastname: Wang
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Bean
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
mesh_terms: 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
chemical_list: D026941:Sodium Channel Blockers; C012647:QX-314; D008012:Lidocaine