title: Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: a systematic study and review.
abstract: OBJECTIVE
  We have developed a strategy to target the permanently charged lidocaine derivative lidocaine N-ethyl bromide (QX-314) selectively into nociceptive sensory neurons through the large-pore transient receptor potential cation channel subfamily V (TRPV1) noxious heat detector channel. This involves co-administration of QX-314 and a TRPV1 agonist to produce a long-lasting local analgesia. For potential clinical use we propose using lidocaine as the TRPV1 agonist, because it activates TRPV1 at clinical doses.
  
  
  METHODS
  We conducted experiments in rats to determine optimal concentrations and ratios of lidocaine and QX-314 that produce the greatest degree and duration of pain-selective block when administered nearby the sciatic nerve: reduction in the response to noxious mechanical (pinch) and to radiant heat stimuli, with minimal disruption in motor function (grip strength).
  
  
  RESULTS
  A combination of 0.5% QX-314 and 2% lidocaine produced 1 h of non-selective sensory and motor block followed by >9 h of pain-selective block, where grip strength was unimpaired. QX-314 at this concentration had no effect by itself, while 2% lidocaine by itself produced 1 h of non-selective block. The combination of 0.5% QX-314 and 2% lidocaine was the best of the many tested, in terms of the duration and selectivity of local analgesia.
  
  
  CONCLUSIONS
  Targeting charged sodium channel blockers into specific sets of axons via activation of differentially expressed large-pore channels provides an opportunity to produce prolonged local analgesia, and represents an example of how exploiting ion channels as a drug delivery port can be used to increase the specificity and efficacy of therapeutics.
authors: FM Kirby Neurobiology Center and Department of Neurology, Children's Hospital, Boston, MA 02115, USA.
authors: D P
authors: DP
authors: Roberson
authors: A M
authors: AM
authors: Binshtok
authors: F
authors: F
authors: Blasl
authors: B P
authors: BP
authors: Bean
authors: C J
authors: CJ
authors: Woolf
mesh_terms: D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D011984:Sensory Receptor Cells / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000700:Analgesics; D026941:Sodium Channel Blockers; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C012647:QX-314; D008012:Lidocaine