Skip to main content
SpringerLink
Log in

Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats

  • Original Article
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

Capsaicin activates a non-specific cation conductance in mammalian sensory neurones. If capsaicin is applied continuously or repeatedly then there is a progressive decline in responsiveness. We have studied the mechanism of this desensitization using electro-physiological methods in cultured dorsal root ganglion neurones from adult rats. The rate of desensitization of capsaicin-induced responses is partly dependent on the extracellular calcium concentration and is slower when extracellular calcium is reduced. Desensitization is strongly inhibited by intracellular application of the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N, N, N′.N′-tetraacetic acid (BAPTA). These data suggest that desensitization is due to a rapid rise in intracellular calcium levels which occurs when capsaicin-sensitive ion channels are activated. Desensitization is not reduced by the non-specific protein kinase inhibitors H7 or staurosporine or by okadaic acid, a selective inhibitor of protein phosphatases 1 and 2A. Desensitization is greatly reduced by cyclosporin A complexed to cyclophilin, which is a specific inhibitor of protein phoshatase 2B (calcineurin). A mechanism for desensitization of capsaicin responsiveness is proposed whereby the evoked rise in calcium activates calcineurin leading to dephosphorylation and desensitization of the capsaicin-sensitive ion channels.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Amann R, Donnerer J, Maggi CA, Giuliani S, DelBianco E, Weihe E, Lembeck F (1990) Capsaicin desensitization in vivo is inhibited by ruthenium red. Eur J Pharmacol 186:169–175

    Article  PubMed  CAS  Google Scholar 

  2. Arbuckle JA, Meigel I, Boddeke HWGM, Docherty RJ (1993) Inhibition of calcineurin reduces desensitization of 5-HT3 receptors in NG108-15 neuroblastoma × glioma hybrid cells. J Physiol 473:267P

    Google Scholar 

  3. Armstrong DL (1989) Calcium channel regulation by calcineurin, a Ca2+-activated phosphatase in mammalian brain. Trends Neurosci 12:117–122

    Article  PubMed  CAS  Google Scholar 

  4. Bevan S, Docherty RJ (1993) Cellular mechanisms of the action of capsaicin. In: Wood JN (ed) Capsaicin in the study of pain. Academic Press, London, pp 27–44

    Google Scholar 

  5. Bevan S, Hothi SK, Hughes G, James IF, Rang HP, Shah KS, Walpole CSJ, Yeats JC (1992) Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin. Br J Pharmacol 107:544–552

    PubMed  CAS  Google Scholar 

  6. Bialojan C, Takai A (1988) Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Biochem J 15:283–290

    Google Scholar 

  7. Chad JE, Eckert R (1986) An enzymatic mechanism for calcium current inactivation in dialyzed Helix neurones. J Physiol (Lond) 378:31–52

    CAS  Google Scholar 

  8. Chen QX, Stelzer A, Kay AR, Wong RKS (1990) GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea-pig hippocampal neurones. J Physiol (Lond) 420:207–221

    CAS  Google Scholar 

  9. Cholewinski A, Burgess GM, Bevan S (1993) The role of calcium in capsaicin-induced desensitization in rat cultured dorsal root ganglion neurons. Neuroscience 55:1015–1023

    Article  PubMed  CAS  Google Scholar 

  10. Clark GD, Clifford DB, Zorumski CF (1990) The effect of agonist concentration, membrane voltage and calcium on N-methyl-D-aspartate receptor desensitization. Neuroscience 39: 787–797

    Article  PubMed  CAS  Google Scholar 

  11. Cooper JA (1987) Effects of cytochalasin and phalloidin on actin. J Cell Biol 105:1473–1478

    Article  PubMed  CAS  Google Scholar 

  12. Docherty RJ, Robertson B, Bevan S (1991) Capsaicin causes prolonged inhibition of voltage-activated calcium currents in adult rat dorsal root ganglion neurons in culture. Neuroscience 40:513–521

    Article  PubMed  CAS  Google Scholar 

  13. Dray A, Bettany J, Foster P (1990) Capsaicin desensitization of peripheral nociceptive fibres does not impair sensitivity to other noxious stimuli. Neurosci Lett 99:50–54

    Article  Google Scholar 

  14. Dray A, Forbes CA, Burgess GM (1990) Ruthenium red blocks the capsaicin-induced increase in intracellular calcium and acti vation of membrane currents in sensory neurons as well as the activation of peripheral nociceptors in vitro. Neurosci Lett 110:52–59

    Article  PubMed  CAS  Google Scholar 

  15. Feltz A, Trautmann A (1982) Desensitization at the frog neuromuscular junction: a biphasic process. J Physiol (Lond) 322:257–272

    CAS  Google Scholar 

  16. Hablitz JJ (1992) Voltage-dependence of GABAA-receptor desensitization in cultured chick cerebral neurons. Synapse 12: 169–171

    Article  PubMed  CAS  Google Scholar 

  17. Heyman I, Rang HP (1985) Depolarizing responses to capsaicin in a subpopulation of rat dorsal root ganglion cells. Neurosci Lett 56:69–75

    Article  PubMed  CAS  Google Scholar 

  18. Holzer P (1991) Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 43:143–201

    PubMed  CAS  Google Scholar 

  19. Legendre P, Rosenmund C, Westbrook GL(1993) Inactivation of NMDA channels in cultured hippocampal neurons by intracellular calcium. J Neurosci 13:674–684

    PubMed  CAS  Google Scholar 

  20. Leiberman DN, Mody I (1994) Regulation of NMDA channel function by endogenous Ca2+-dependent phosphatase. Nature 369:235–239

    Article  Google Scholar 

  21. Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schrieber SL (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66:807–815

    Article  PubMed  CAS  Google Scholar 

  22. Magazanik LG, Vyskocil F (1970) Dependence of acetylcholine desensitization on the membrane potential of frog muscle fibres and on the ionic changes in the medium. J Physiol (Lond) 210:507–518

    CAS  Google Scholar 

  23. Maggi CA, Patacchini R, Santicioli P, Giuliani S, Geppetti P, Meli A (1988) Protective action of ruthenium red towards capsaicin desensitization of sensory fibres. Neurosci Lett 88: 201–205

    Article  PubMed  CAS  Google Scholar 

  24. Marsh SJ, Stansfield CE, Brown DA, Davy R, McCarthy D (1987) The mechanism of action of capsaicin on sensory C-type neurones and their axons in vitro. Neuroscience 23:275–289

    Article  PubMed  CAS  Google Scholar 

  25. Mathie A, Colquhoun D, Cull-Candy SG (1990) Rectification of currents activated by nicotinic acetylcholine receptors in rat sympathetic ganglion neurones. J Physiol (Lond) 427:625–655

    CAS  Google Scholar 

  26. Mayer ML, MacDermott AB, Westbrook GL, Smith SJ, Barker JL (1987) Agonist- and voltage-gated calcium entry in cultured mouse spinal cord neurons under voltage clamp measured using arsezano III. J Neurosci 7:3230–3244

    PubMed  CAS  Google Scholar 

  27. Mayer ML, Vyklicky L, Clements J (1989) Regulation of NMDA receptor desensitization in mouse hippocampal neurones by glycine. Nature 338:425–427

    Article  PubMed  CAS  Google Scholar 

  28. McDonald JF, Mody I, Salter MW (1989) Regulation of N-methyl-D-aspartate receptors revealed by intracellular dialysis of murine neurones in culture. J Physiol (Lond) 414:17–34

    Google Scholar 

  29. Neijt HC, Plomp JJ, Vijverberg HPM (1989) Kinetics of the membrane current mediated by serotonin 5-HT3 receptors in cultured mouse neuroblastoma cells. J Physiol (Lond) 411: 257–269

    CAS  Google Scholar 

  30. Oh DJ, Dichter MA (1992) Desensitization of GABA-induced currents in cultured rat hippocampal neurons. Neuroscience 49:571–576

    Article  PubMed  CAS  Google Scholar 

  31. Rosenmund C, Westbrook GL (1993) Rundown of N-methyl-D-aspartate channels during whole-cell recording in rat hippocampal neurons: role of Ca2+and ATP. J Physiol (Lond) 470:705–729

    CAS  Google Scholar 

  32. Rosenmund C, Westbrook GL (1993) Calcium-induced actin depolymerization reduces NMDA channel activity. Neuron 10: 805–814

    Article  PubMed  CAS  Google Scholar 

  33. Ruegg UT, Burgess GM (1989) Staurosporine, K-252 and UCN-01: potent but non-specific inhibitors of protein kinases. Trends Pharmacol Sci 10:218–220

    Article  PubMed  CAS  Google Scholar 

  34. Santicioli P, Patacchini R, Maggi CA, Meli A (1987) Exposure to calcium-free medium protects sensory fibres by capsaicin desensitization. Neurosci Lett 80:167–172

    Article  PubMed  CAS  Google Scholar 

  35. Tong G, Shepherd D, Jahr CE (1995) Synaptic desenstization of NMDA receptors by calcineurin. Science 267:1510–1512

    Article  PubMed  CAS  Google Scholar 

  36. Trussell LO, Thio LL, Zorumski CF, Fischbach GD (1988) Rapid desensitization of glutamate receptors in vertebrate central neurones. Proc Natl Acad Sci USA 85:2834–2838

    Article  PubMed  CAS  Google Scholar 

  37. Tsien RY (1980) New calcium indicators and buffers with high selectivity against magnesium and protons: design, synthesis and properties of prototype structures. Biochemistry 19:2396–2404

    Article  PubMed  CAS  Google Scholar 

  38. Vicent SR (1994) Nitric oxide: a radical neurotransmitter in the central nervous system. Prog Neurobiol 42:129–160

    Article  Google Scholar 

  39. Wang L-Y, Orser BA, Brautigan DL, McDonald JF (1994) Regulation of NMDA receptors in cultured hippocampal neurons by protein phosphatases 1 and 2A. Nature 369: 230–232

    Article  PubMed  CAS  Google Scholar 

  40. Wang YT, Salter MW (1994) Regulation of NMDA receptors by tyrosine kinases and phosphatases. Nature 369:233–235

    Article  PubMed  CAS  Google Scholar 

  41. Winter J, Dray A, Wood JN, Yeats JC, Bevan S (1990) Cellular mechanism of action of resiniferatoxin: a potent sensory neuron excitotoxin. Brain Res 520:131–140

    Article  PubMed  CAS  Google Scholar 

  42. Wood JN, Winter J, James IF, Rang HP, Yeats JC, Bevan S (1988) Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture. J Neurosci 8:3208–3220

    PubMed  CAS  Google Scholar 

  43. Yakel JL, Shao XM, Jackson MB (1991) Activation and desensitization of the 5-HT3 receptor in a rat glioma × mouse neuroblastoma hybrid cell. J Physiol (Lond) 436:293–308

    CAS  Google Scholar 

  44. Yakel JL, Lagrutta A, Adelman JP, North RA (1993) Single amino acid substitution affects desensitization of the 5-hydroxy-tryptamine type 3 receptor expressed in Xenopus oocytes. Proc Natl Acad Sci USA 90:5030–5033

    Article  PubMed  CAS  Google Scholar 

  45. Yeats JC, Boddeke HWGM, Docherty RJ (1992) Capsaicin desensitization in rat dorsal root ganglion neurones is due to activation of calcineurin. Br J Pharmacol 107:238P

    Google Scholar 

  46. Yeats JC, Docherty RJ, Bevan S (1992) Calcium-dependent and independent desensitization of capsaicin-evoked responses in voltage-clamped adult rat dorsal root ganglion (DRG) neurones in culture. J Physiol (Lond) 446:390P

    Google Scholar 

  47. Zhang X, Verge V, Wiesenfeld-Hallin Z, Ju G, Bredt D, Synder SH, Hokfelt T (1993) Nitric oxide synthase-like immunoreactivity in lumbar dorsal root ganglia and spinal cord of rat and monkey and effect of peripheral axotomy. J Comp Neurol 335:563–575

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sandoz Institute for Medical Research, 5 Gower P1, WC1E6BN, London, UK

    R. J. Docherty, J. C. Yeats & S. Bevan

  2. Preclinical Research, CH-4002, Sandoz Pharma, Basel, Switzerland

    H. W. G. M. Boddeke

Authors
  1. R. J. Docherty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. C. Yeats
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Bevan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. W. G. M. Boddeke
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Docherty, R.J., Yeats, J.C., Bevan, S. et al. Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats. Pflügers Arch. 431, 828–837 (1996). https://doi.org/10.1007/s004240050074

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s004240050074

Key words

Search

Navigation