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Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers.
Nature. 2007 Oct 04; 449(7162):607-10.Nat

Abstract

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 membrane. 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.

Authors+Show Affiliations

Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17914397

Citation

Binshtok, Alexander M., et al. "Inhibition of Nociceptors By TRPV1-mediated Entry of Impermeant Sodium Channel Blockers." Nature, vol. 449, no. 7162, 2007, pp. 607-10.
Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature. 2007;449(7162):607-10.
Binshtok, A. M., Bean, B. P., & Woolf, C. J. (2007). Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature, 449(7162), 607-10.
Binshtok AM, Bean BP, Woolf CJ. Inhibition of Nociceptors By TRPV1-mediated Entry of Impermeant Sodium Channel Blockers. Nature. 2007 Oct 4;449(7162):607-10. PubMed PMID: 17914397.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. AU - Binshtok,Alexander M, AU - Bean,Bruce P, AU - Woolf,Clifford J, PY - 2007/06/21/received PY - 2007/08/28/accepted PY - 2007/10/5/pubmed PY - 2007/11/2/medline PY - 2007/10/5/entrez SP - 607 EP - 10 JF - Nature JO - Nature VL - 449 IS - 7162 N2 - 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 membrane. 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. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/17914397/Inhibition_of_nociceptors_by_TRPV1_mediated_entry_of_impermeant_sodium_channel_blockers_ L2 - https://doi.org/10.1038/nature06191 DB - PRIME DP - Unbound Medicine ER -