Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: a systematic study and review.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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).

KEY 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 AND IMPLICATIONS:

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: D P Roberson, A M Binshtok, F Blasl, B P Bean, C J Woolf
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 164 Issue 1 Pg. 48-58 (Sep 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 21457220 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• Analgesics
• Sodium Channel Blockers
• TRPV Cation Channels
• Trpv1 protein, rat
• QX-314
• Lidocaine

Topics

• Analgesics (pharmacokinetics, pharmacology)
• Animals
• Drug Delivery Systems (methods)
• Lidocaine (analogs & derivatives, pharmacokinetics, pharmacology)
• Male
• Nociceptors (drug effects, metabolism)
• Pain (drug therapy, metabolism)
• Rats
• Sensory Receptor Cells (metabolism)
• Sodium Channel Blockers (pharmacokinetics, pharmacology)
• TRPV Cation Channels (antagonists & inhibitors, metabolism)