Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers (original) (raw)

Nature volume 449, pages 607–610 (2007)Cite this article

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 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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References

  1. Hille, B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J. Gen. Physiol. 69, 497–515 (1977)
    Article CAS Google Scholar
  2. Caterina, M. J. & Julius, D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. 24, 487–517 (2001)
    Article CAS Google Scholar
  3. Meyers, J. R. et al. Lighting up the senses: FM1-43 loading of sensory cells through nonselective ion channels. J. Neurosci. 23, 4054–4065 (2003)
    Article CAS Google Scholar
  4. Frazier, D. T., Narahashi, T. & Yamada, M. The site of action and active form of local anesthetics. II. Experiments with quaternary compounds. J. Pharmacol. Exp. Ther. 171, 45–51 (1970)
    CAS PubMed Google Scholar
  5. Strichartz, G. R. The inhibition of sodium currents in myelinated nerve by quaternary derivatives of lidocaine. J. Gen. Physiol. 62, 37–57 (1973)
    Article CAS Google Scholar
  6. Yeh, J. Z. Sodium inactivation mechanism modulates QX-314 block of sodium channels in squid axons. Biophys. J. 24, 569–574 (1978)
    Article ADS CAS Google Scholar
  7. Cahalan, M. D. & Almers, W. Interactions between quaternary lidocaine, the sodium channel gates, and tetrodotoxin. Biophys. J. 27, 39–55 (1979)
    Article ADS CAS Google Scholar
  8. Qu, Y., Rogers, J., Tanada, T., Scheuer, T. & Catterall, W. A. Molecular determinants of drug access to the receptor site for antiarrhythmic drugs in the cardiac Na+ channel. Proc. Natl Acad. Sci. USA 92, 11839–11843 (1995)
    Article ADS CAS Google Scholar
  9. Liu, L., Oortgiesen, M., Li, L. & Simon, S. A. Capsaicin inhibits activation of voltage-gated sodium currents in capsaicin-sensitive trigeminal ganglion neurons. J. Neurophysiol. 85, 745–758 (2001)
    Article CAS Google Scholar
  10. Sluka, K. A. & Willis, W. D. The effects of G-protein and protein kinase inhibitors on the behavioral responses of rats to intradermal injection of capsaicin. Pain 71, 165–178 (1997)
    Article CAS Google Scholar
  11. Owsianik, G., Talavera, K., Voets, T. & Nilius, B. Permeation and selectivity of TRP channels. Annu. Rev. Physiol. 68, 685–717 (2006)
    Article CAS Google Scholar
  12. Hellwig, N. et al. TRPV1 acts as proton channel to induce acidification in nociceptive neurons. J. Biol. Chem. 279, 34553–34561 (2004)
    Article CAS Google Scholar
  13. Sunami, A., Glaaser, I. W. & Fozzard, H. A. A critical residue for isoform difference in tetrodotoxin affinity is a molecular determinant of the external access path for local anesthetics in the cardiac sodium channel. Proc. Natl Acad. Sci. USA 97, 2326–2331 (2000)
    Article ADS CAS Google Scholar
  14. Amaya, F. et al. The voltage-gated sodium channel Nav1.9 is an effector of peripheral inflammatory pain hypersensitivity. J. Neurosci. 26, 12852–12860 (2006)
    Article CAS Google Scholar
  15. Hargreaves, K., Dubner, R., Brown, F., Flores, C. & Joris, J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32, 77–88 (1988)
    Article CAS Google Scholar
  16. Hara, K., Saito, Y., Kirihara, Y. & Sakura, S. The interaction between γ-aminobutyric acid agonists and diltiazem in visceral antinociception in rats. Anesth. Analg. 98, 1380–1384 (2004)
    Article CAS Google Scholar

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Acknowledgements

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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Authors and Affiliations

  1. Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA,
    Alexander M. Binshtok & Clifford J. Woolf
  2. Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA,
    Bruce P. Bean

Authors

  1. Alexander M. Binshtok
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  2. Bruce P. Bean
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  3. Clifford J. Woolf
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Corresponding author

Correspondence toBruce P. Bean.

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The authors declare no competing financial interests.

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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). https://doi.org/10.1038/nature06191

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Editorial Summary

Hit where it hurts

The snag with most local anaesthetics is their lack of specificity. They are lipophilic, so can enter virtually any neuron, where they indiscriminately block sodium channels in the membrane. A way of blocking the activity of specific pain-sensing neurons without affecting other sensory or motor neurons could be used to create a more targeted form of local anaesthesia, and that is the prospect held out by Binshtok et al. in this issue. They report that the lidocaine derivative QX-314 can be targeted to pain-sensing neurons. Normally QX-314 can't cross the cell membrane. But antipain specificity is ensured by allowing it to enter via the TRPV1 channel, a capsaicin receptor found only in pain-sensing neurons. Co-application of QX-314 and capsaicin in rats blocked mechanical and thermal pain, inducing local anaesthesia, without the paralysis seen in 'normal' lidocaine anaesthesia.

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