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Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers


Most local anaesthetics used clinically are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane1. These anaesthetics block sodium channels and thereby the excitability of all neurons, not just sensory neurons. We tested the possibility of selectively blocking the excitability of primary sensory nociceptor (pain-sensing) neurons by introducing the charged, membrane-impermeant lidocaine derivative QX-314 through the pore of the noxious-heat-sensitive TRPV1 channel. Here we show that charged sodium-channel blockers can be targeted into nociceptors by the application of TRPV1 agonists to produce a pain-specific local anaesthesia. QX-314 applied externally had no effect on the activity of sodium channels in small sensory neurons when applied alone, but when applied in the presence of the TRPV1 agonist capsaicin, QX-314 blocked sodium channels and inhibited excitability. Inhibition by co-applied QX-314 and capsaicin was restricted to neurons expressing TRPV1. Injection of QX-314 together with capsaicin into rat hindpaws produced a long-lasting (more than 2 h) increase in mechanical and thermal nociceptive thresholds. Long-lasting decreases in pain sensitivity were also seen with regional injection of QX-314 and capsaicin near the sciatic nerve; however, in contrast to the effect of lidocaine, the application of QX-314 and capsaicin together was not accompanied by motor or tactile deficits.

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Figure 1: Application of extracellular QX-314 (5 mM) and capsaicin (1 μM) together selectively blocks sodium currents in capsaicin-responsive DRG neurons.
Figure 2: Application of QX-314 and capsaicin together blocks excitability in nociceptor neurons.
Figure 3: Intraplantar injection of capsaicin and QX-314 together produces prolonged local anaesthesia to mechanical (von Frey) and thermal noxious stimuli.
Figure 4: Injection of QX-314 followed by capsaicin adjacent to the sciatic nerve anaesthetized the animals to noxious mechanical and thermal stimuli of the hindlimbs without producing any motor deficit.


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We thank T. Herbert and S. Lin for technical assistance.

Author Contributions B.P.B. conceived of introducing charged ion channel blockers through TRPV1 channels; A.M.B., C.J.W. and B.P.B. designed the experiments; A.M.B. did all experiments; and A.M.B., B.P.B. and C.J.W. wrote the paper.

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Correspondence to Bruce P. Bean.

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Binshtok, A., Bean, B. & Woolf, C. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 449, 607–610 (2007).

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