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

Abstract

BACKGROUND AND PURPOSEWe 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 APPROACHWe 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 RESULTSA 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 IMPLICATIONSTargeting 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.

Permeation and block of TRPV1 channels by the cationic lidocaine derivative QX-314

“…These experiments were motivated by the concept of using TRPV1 channels as portals for delivering charged drug molecules into primary pain-sensing neurons to inhibit pain signaling in vivo selectively Kim et al 2010;Liu et al 2011;Roberson et al 2011), an approach recently extended to using light-controlled QX-314 derivatives (Mourot et al 2012) and to using TRPA1 channels as portals (Lennertz et al 2012). Our finding that QX-314 can enter through the standard pore and does not require pore dilation is likely advantageous for in vivo and potential clinical use because pore dilation typically requires large concentrations of agonist (Banke et al 2010;Chung et al 2008), which may be difficult to deliver and maintain in vivo (e.g., using perineural infusion to produce nerve block).…”

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…Specifically, coadministration of capsaicin with a local anesthetic enhances TRPV1 pore dilation to facilitate the delivery of membrane impermeant local anesthetics to voltagedependent sodium channels, which inhibits action potentials in TRPV1-positive sensory neurons (Binshtok et al, 2007). This represents a novel means of exploiting ion channels for drug delivery that may be used to increase the specificity and efficacy of therapeutics (Roberson et al, 2011). This approach has also been used to investigate distinct neuronal itch pathways and indicates the potential to selectively inhibit pain-transmitting nerves where inflammatory states have increased TRP channel expression (Roberson et al, 2013).…”

Differential analgesic effects of subanesthetic concentrations of lidocaine on spontaneous and evoked pain in human painful neuroma: A randomized, double blind study

“…Lidocaine selectively inhibits the spontaneous ectopic activity by binding to Na-channels [39] in their inactivated form and thereby blocks nociceptive transmission [40], but lacks the selective specificity on the sodium channels subtypes. Lidocaine injection close to a nerve at a concentration of 1-2% (35-69 mM) [41,42] induced complete sensory and motor block. The suppression of neuropathic pain by subanesthetic concentrations of lidocaine is well know, but it is widely believed to work by blocking axonal conduction, but blocking the impulse initiation requires far lower concentrations than blocking the axonal propagation of nerve impulses that have already formed.…”