Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: a systematic study and review - PubMed (original) (raw)

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

D P Roberson et al. Br J Pharmacol. 2011 Sep.

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.

© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

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Figures

Figure 4

Figure 4

The motor and sensory block following injection of 1% lidocaine N-ethyl bromide (QX-314) is abolished when injected in the absence of general anaesthesia. Perisciatic application of 1% QX-314 alone produces prolonged elevation in thermal (radiant heat, 50°C) response latency (A), pinch tolerance threshold (B) and grip weakness (C) only while applied under isoflurane-induced general anaesthesia. Perisciatic injection of 1% QX-314 in non-anaesthetized animals did not change the responses to noxious mechanical and thermal stimuli or grip force. Application of vehicle (0.9% NaCl) administered without general anaesthesia also did not alter motor, mechanical or thermal responsiveness. Values expressed as percent of maximal block (mean ± SEM; *P < 0.01, †P < 0.01,

anova

followed by Dunnett's test; n = 9 for each group). All injections administered at time 0.

Figure 1

Figure 1

The duration of the elevation in thermal response latency (radiant heat, 50°C), pinch tolerance threshold and reduction in grip strength produced following perisciatic injection of lidocaine HCl (1%, 1.5%, 2%) and vehicle (0.9% NaCl) (mean ± SEM; *P < 0.01). All injections administered under isoflurane-induced general anaesthesia at time 0.

Figure 2

Figure 2

The duration of the elevation in thermal (radiant heat, 50°C) response latency (A, D and G), pinch tolerance threshold (B, E and H), and reduction in grip strength (C, F and I) produced following perisciatic (200 µL) injection of lidocaine alone (1%, 1.5% or 2%), 0.5% lidocaine N-ethyl bromide (QX-314) alone, or 0.5% QX-314 administered together with lidocaine (1%, 1.5% or 2%) (mean ± SEM; *P < 0.01). All injections administered under isoflurane-induced general anaesthesia at time 0.

Figure 3

Figure 3

Analysis of the change in grip strength, thermal (radiant heat, 50°C) response latency and pinch tolerance threshold produced following perisciatic injection of varying doses of lidocaine N-ethyl bromide (QX-314) (0%, 0.5%) and lidocaine (0%, 1%, 2%) expressed as total area under the curve (AUC). Note that the value of AUC representing change in pinch tolerance threshold in the group receiving a combined dose of 0.5% QX-314 + 2% lidocaine, is greater than the combined values of corresponding AUCs from the group receiving 0.5% QX-314 alone plus the AUC from the group receiving 2.0% lidocaine alone. Similarly, the AUC value representing change in thermal latency in the group receiving a combined dose of 0.5% QX-314 + 2% lidocaine, is much greater than the combined values of corresponding AUCs from the group receiving 0.5% QX-314 alone plus the AUC from the group receiving 2.0% lidocaine alone. Conversely, the value of AUC representing grip strength in the group receiving a combined dose of 0.5% QX-314 + 2% lidocaine, is less than the combined values of grip strength AUCs from the group receiving 0.5% QX-314 alone plus the grip strength AUC from the group receiving 2.0% lidocaine alone.

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