Skip to main content

Topical antiseptics for the treatment of sore throat block voltage-gated neuronal sodium channels in a local anaesthetic-like manner

Abstract

Lozenges for the treatment of sore throat provide relief of discomfort in cases of oral inflammation. This effect has not been fully explained so far. Here, we have examined the proposition that key components of pharmaceutical preparations for the treatment of sore throat which are routinely regarded antiseptics might have sodium channel-blocking, i.e. local anaesthetic-like effects. We investigated the effects of hexylresorcinol, amylmetacresol and dichloro-benzylalcohol on voltage-operated neuronal (NaV1.2) sodium channels heterologously expressed in HEK 293 cells in vitro. Hexylresorcinol, amylmetacresol and dichloro-benzylalcohol reversibly blocked depolarisation-induced whole-cell sodium inward currents. The half-maximum blocking concentrations (EC50) at −150 mV were 23.1, 53.6 and 661.6 µM, respectively. Block induced by hexylresorcinol and amylmetacresol was increased at depolarised potentials and use-dependent during trains of depolarisations applied at high frequency (100 Hz) indicating that both drugs bind more tightly to inactivated conformations of the channel. Estimates for the inactivated state affinity were 1.88 and 35 µM for hexylresorcinol and amylmetacresol, respectively. Hexylresorcinol and amylmetacresol are 10–20 fold more potent than the local anaesthetic lidocaine in blocking sodium inward current. Both drugs show an increased effect at depolarised membrane potentials or in conditions of high-frequency discharges.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Amir R, Argoff CE, Bennett GJ, Cummins TR, Durieux ME, Gerner P, Gold MS, Porreca F, Strichartz GR (2006) The role of sodium channels in chronic inflammatory and neuropathic pain. J Pain 7:S1–S29

    PubMed  Article  CAS  Google Scholar 

  2. Baker MD, Wood JN (2001) Involvement of Na+ channels in pain pathways. Trends Pharmacol Sci 22:27–31

    PubMed  Article  CAS  Google Scholar 

  3. Balser JR, Nuss HB, Romashko DN, Marban E, Tomaselli GF (1996) Functional consequences of lidocaine binding to slow-inactivated sodium channels. J Gen Physiol 107:643–658

    PubMed  Article  CAS  Google Scholar 

  4. Bean BP, Cohen CJ, Tsien RW (1983) Lidocaine block of cardiac sodium channels. J Gen Physiol 81:613–642

    PubMed  Article  CAS  Google Scholar 

  5. Berry P (2008) Rapid relief of acute sore throat with Strepsils lozenges: a single-blind comparative study. Royal Society of Medicine Press, London. ISBN 978-1-85315-869-8

    Google Scholar 

  6. Bonhaus DW, Herman RC, Brown CM, Cao Z, Chang LF, Loury DN, Sze P, Zhang L, Hunter JC (1996) The beta 1 sodium channel subunit modifies the interactions of neurotoxins and local anesthetics with the rat brain IIA alpha sodium channel in isolated membranes but not in intact cells. Neuropharmacology 35:605–613

    PubMed  Article  CAS  Google Scholar 

  7. Catterall WA (1992) Cellular and molecular biology of voltage-gated sodium channels. Physiol Rev 72:S15–S48

    PubMed  CAS  Google Scholar 

  8. Chahine M, Bennett PB, George AL Jr, Horn R (1994) Functional expression and properties of the human skeletal muscle sodium channel. Pflugers Arch 427:136–142

    PubMed  Article  CAS  Google Scholar 

  9. Fan Z, George AL Jr, Kyle JW, Makielski JC (1996) Two human paramyotonia congenita mutations have opposite effects on lidocaine block of Na+ channels expressed in a mammalian cell line. J Physiol 496(Pt 1):275–286

    PubMed  CAS  Google Scholar 

  10. Graham FL, van der Eb AJ (1973) A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 52:456–467

    PubMed  Article  CAS  Google Scholar 

  11. Haeseler G, Leuwer M, Kavan J, Würz A, Dengler R, Piepenbrock S (1999) Voltage-dependent block of normal and mutant muscle sodium channels by 4-chloro-m-cresol. Br J Pharmacol 128(6):1259–1267

    PubMed  Article  CAS  Google Scholar 

  12. Haeseler G, Mamarvar M, Bufler J, Dengler R, Hecker H, Aronson JK, Piepenbrock S, Leuwer M (2000a) Voltage-dependent blockade of normal and mutant muscle sodium channels by benzylalcohol. Br J Pharmacol 130:1321–1330

    PubMed  Article  CAS  Google Scholar 

  13. Haeseler G, Petzold J, Hecker H, Wurz A, Dengler R, Piepenbrock S, Leuwer M (2000b) Succinylcholine metabolite succinic acid alters steady state activation in muscle sodium channels. Anesthesiology 92:1385–1391

    PubMed  Article  CAS  Google Scholar 

  14. Haeseler G, Piepenbrink A, Bufler J, Dengler R, Aronson JK, Piepenbrock S, Leuwer M (2001a) Structural requirements for voltage-dependent block of muscle sodium channels by phenol derivatives. Br J Pharmacol 132:1916–1924

    PubMed  Article  CAS  Google Scholar 

  15. Haeseler G, Störmer M, Bufler J, Dengler R, Hecker H, Piepenbrock S, Leuwer M (2001b) Propofol blocks human skeletal muscle sodium channels in a voltage-dependent manner. Anesth Analg 92(5):1192–1198

    PubMed  Article  CAS  Google Scholar 

  16. Haeseler G, Gudehus S, Bufler J, Dengler R, Leuwer M (2006) High-affinity blockade of voltage-operated skeletal muscle sodium channels by 2, 6-dimethyl-4-chlorophenol. Eur J Anaesthesiol 23(3):190–196

    PubMed  Article  CAS  Google Scholar 

  17. Haeseler G, Karst M, Foadi N, Gudehus S, Roeder A, Hecker H, Dengler R, Leuwer M (2008) High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues. Br J Pharmacol 155:265–275

    PubMed  Article  CAS  Google Scholar 

  18. Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch 391:85–100

    PubMed  Article  CAS  Google Scholar 

  19. Hammarstrom AK, Gage PW (1998) Inhibition of oxidative metabolism increases persistent sodium current in rat CA1 hippocampal neurons. J Physiol 510(Pt 3):735–741

    PubMed  Article  Google Scholar 

  20. Isom LL, De Jongh KS, Patton DE, Reber BF, Offord J, Charbonneau H, Walsh K, Goldin AL, Catterall WA (1992) Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel. Science 256:839–842

    PubMed  Article  CAS  Google Scholar 

  21. Ju YK, Saint DA, Gage PW (1996) Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol 497(Pt 2):337–347

    PubMed  CAS  Google Scholar 

  22. Lai J, Porreca F, Hunter JC, Gold MS (2004) Voltage-gated sodium channels and hyperalgesia. Annu Rev Pharmacol Toxicol 44:371–397

    PubMed  Article  CAS  Google Scholar 

  23. Leuwer M, Haeseler G, Hecker H, Bufler J, Dengler R, Aronson JK (2004) An improved model for the binding of lidocaine and structurally related local anaesthetics to fast-inactivated voltage-operated sodium channels, showing evidence of cooperativity. Br J Pharmacol 141:47–54

    PubMed  Article  CAS  Google Scholar 

  24. Makielski JC, Limberis J, Fan Z, Kyle JW (1999) Intrinsic lidocaine affinity for Na channels expressed in Xenopus oocytes depends on alpha (hH1 vs. rSkM1) and beta 1 subunits. Cardiovasc Res 42:503–509

    PubMed  Article  CAS  Google Scholar 

  25. Mitrovic N, George AL Jr, Heine R, Wagner S, Pika U, Hartlaub U, Zhou M, Lerche H, Fahlke C, Lehmann-Horn F (1994) K(+)-aggravated myotonia: destabilization of the inactivated state of the human muscle Na+ channel by the V1589M mutation. J Physiol 478(Pt 3):395–402

    PubMed  CAS  Google Scholar 

  26. Moran O, Nizzari M, Conti F (2000) Endogenous expression of the beta1A sodium channel subunit in HEK-293 cells. FEBS Lett 473:132–134

    PubMed  Article  CAS  Google Scholar 

  27. Pu J, Balser JR, Boyden PA (1998) Lidocaine action on Na+ currents in ventricular myocytes from the epicardial border zone of the infarcted heart. Circ Res 83:431–440

    PubMed  CAS  Google Scholar 

  28. Rogawski MA, Loscher W (2004) The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat Med 10:685–692

    PubMed  Article  CAS  Google Scholar 

  29. Sarkar SN, Adhikari A, Sikdar SK (1995) Kinetic characterization of rat brain type IIA sodium channel alpha-subunit stably expressed in a somatic cell line. J Physiol 488(Pt 3):633–645

    PubMed  CAS  Google Scholar 

  30. Takahashi N, Kikuchi S, Dai Y, Kobayashi K, Fukuoka T, Noguchi K (2003) Expression of auxiliary beta subunits of sodium channels in primary afferent neurons and the effect of nerve injury. Neuroscience 121:441–450

    PubMed  Article  CAS  Google Scholar 

  31. Vedantham V, Cannon SC (1999) The position of the fast-inactivation gate during lidocaine block of voltage-gated Na+ channels. J Gen Physiol 113:7–16

    PubMed  Article  CAS  Google Scholar 

  32. Wade AG (2008) A randomized, double-blind, parallel-group, placebo-controlled, multiple-dose study of the efficacy of Strepsils lozenges in the relief of acute sore-throat. Royal Society of Medicine Press, London. ISBN 978-1-85315-869-8

    Google Scholar 

  33. Wang DW, George AL Jr, Bennett PB (1996) Comparison of heterologously expressed human cardiac and skeletal muscle sodium channels. Biophys J 70:238–245

    PubMed  Article  CAS  Google Scholar 

  34. Waxman SG, Hains BC (2006) Fire and phantoms after spinal cord injury: Na+ channels and central pain. Trends Neurosci 29:207–215

    PubMed  Article  CAS  Google Scholar 

  35. Wright SN, Wang SY, Kallen RG, Wang GK (1997) Differences in steady-state inactivation between Na channel isoforms affect local anesthetic binding affinity. Biophys J 73:779–788

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

We are indebted to Prof. Frank Lehmann-Horn, Ulm, Germany, for providing us with transfected cells, to Jobst Kilian and Andreas Niesel, Dept. of Neurology, Hannover, Germany, for technical support and to Irene Wirszins, Dept. of Anaesthesiology, Hannover, Germany, for taking care of the cell culture.

Statement of conflict of interest

This work was supported by an unrestricted grant from Reckitt Benckiser to Martin Leuwer.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jörg Ahrens.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Buchholz, V., Leuwer, M., Ahrens, J. et al. Topical antiseptics for the treatment of sore throat block voltage-gated neuronal sodium channels in a local anaesthetic-like manner. Naunyn-Schmied Arch Pharmacol 380, 161–168 (2009). https://doi.org/10.1007/s00210-009-0416-x

Download citation

Keywords

  • Sodium channels
  • Voltage-operated
  • Local anaesthetic
  • Hexylresorcinol
  • Amylmetacresol
  • Dichloro-benzylalcohol