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Specificity of cold thermotransduction is determined by differential ionic channel expression

Nature Neuroscience volume 5, pages 254–260 (2002)Cite this article

Abstract

Sensations of cold are mediated by specific thermoreceptor nerve endings excited by low temperature and menthol. Here we identify a population of cold-sensitive cultured mouse trigeminal ganglion neurons with a unique set of biophysical properties. Their impulse activity during cooling and menthol application was similar to that of cold thermoreceptor fibers in vivo. We show that cooling closes a background K+ channel, causing depolarization and firing that is limited by the slower reduction of a cationic inward current (Ih). In cold-insensitive neurons, firing is prevented by a slow, transient, 4-AP-sensitive K+ current (IKD) that acts as an excitability brake. In addition, pharmacological blockade of IKD induced thermosensitivity in cold-insensitive neurons, a finding that may explain cold allodynia in neuropathic pain. These results suggest that cold sensitivity is not associated to a specific transduction molecule but instead results from a favorable blend of ionic channels expressed in a small subset of sensory neurons.

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Figure 1: Identification and characterization of cold-sensitive (CS) neurons.
Figure 2: Electrophysiological properties of cold-sensitive (CS) and -insensitive (CI) neurons.
Figure 3: Effect of cold temperature on ionic conductances.
Figure 4: Differential expression of ionic currents in cold-sensitive (CS) and -insensitive (CI) neurons and induction of cold thermosensitivity by K+-channel blockers.

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References

  1. Yarnitsky, D. & Ochoa, J. L. Warm and cold specific somatosensory systems. Psychophysical thresholds, reaction times and peripheral conduction velocities. Brain 114, 1819–1826 (1991).

    Article  Google Scholar 

  2. Craig, A. D., Chen, K., Bandy, D. & Reiman, E. M. Thermosensory activation of insular cortex. Nat. Neurosci. 3, 184–190 (2000).

    Article  CAS  Google Scholar 

  3. Han, Z. S., Zhang, E. T. & Craig, A. D. Nociceptive and thermoreceptive lamina I neurons are anatomically distinct. Nat. Neurosci. 1, 218–225 (1998).

    Article  CAS  Google Scholar 

  4. Hensel, H. & Zotterman, Y. The response of the cold receptors to constant cooling. Acta. Physiol. Scan. 22, 96–113 (1951).

    Article  CAS  Google Scholar 

  5. Hensel, H. & Iggo, A. Analysis of cutaneous warm and cold fibres in primates. Pflugers Arch. 329, 1–8 (1971).

    Article  CAS  Google Scholar 

  6. Kenshalo, D. R. & Gallegos, E. S. Multiple temperature-sensitive spots innervated by single nerve fibers. Science 158, 1064–1065 (1967).

    Article  CAS  Google Scholar 

  7. Hensel, H., Iggo, A. & Witt, I. A quantitative study of sensitive cutaneous thermoreceptors with C afferent fibers. J. Physiol. 153, 113–126 (1960).

    Article  CAS  PubMed Central  Google Scholar 

  8. Gallar, J., Pozo, M. A., Tuckett, R. P. & Belmonte, C. Response of sensory units with unmyelinated fibres to mechanical, thermal and chemical stimulation of the cat's cornea. J. Physiol. 468, 609–622 (1993).

    Article  CAS  PubMed Central  Google Scholar 

  9. Brock, J., Pianova, S. & Belmonte, C. Differences between nerve terminal impulses of polymodal nociceptors and cold sensory receptors of the guinea-pig cornea. J. Physiol. 533, 493–501 (2001).

    Article  CAS  PubMed Central  Google Scholar 

  10. McCleskey, E. W. Thermoreceptors: recent heat in thermosensation. Curr. Biol. 7, R679–R681 (1997).

    Article  CAS  Google Scholar 

  11. Cesare, P. & McNaughton, P. A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin. Proc. Natl. Acad. Sci. USA 93, 15435–15439 (1996).

    Article  CAS  Google Scholar 

  12. Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).

    Article  CAS  Google Scholar 

  13. Pierau, F. K., Torrey, P. & Carpenter, D. Effect of ouabain and potassium-free solution on mammalian thermosensitive afferents in vitro. Pflugers Arch. 359, 349–356 (1975).

    Article  CAS  Google Scholar 

  14. Hensel, H. Functional and structural basis of thermoreception. Prog. Brain Res. 43, 105–118 (1976).

    Article  CAS  Google Scholar 

  15. Spray, D. C. Metabolic dependence of frog cold receptor sensitivity. Brain Res. 72, 354–359 (1974).

    Article  CAS  Google Scholar 

  16. Carpenter, D. O. Ionic and metabolic bases of neuronal thermosensitivity. Fed. Proc. 40, 2808–2813 (1981).

    CAS  PubMed  Google Scholar 

  17. Spray, D. C. Cutaneous temperature receptors. Annu. Rev. Physiol. 48, 625–638 (1986).

    Article  CAS  Google Scholar 

  18. Maingret, F. et al. TREK-1 is a heat-activated background K(+) channel. EMBO J. 19, 2483–2491 (2000).

    Article  CAS  PubMed Central  Google Scholar 

  19. Reid, G. & Flonta, M. Cold transduction by inhibition of a background potassium conductance in rat primary sensory neurones. Neurosci. Lett. 297, 171–174 (2001).

    Article  CAS  Google Scholar 

  20. Reid, G. & Flonta, M. L. Physiology. Cold current in thermoreceptive neurons. Nature 413, 480 (2001).

  21. Hensel, H., Andres, K. H. & von During, M. Structure and function of cold receptors. Pflugers Arch. 352, 1–10 (1974).

    Article  CAS  Google Scholar 

  22. Brock, J. A., McLachlan, E. M. & Belmonte, C. Tetrodotoxin-resistant impulses in single nociceptor nerve terminals in guinea-pig cornea. J. Physiol. 512, 211–217 (1998).

    Article  CAS  PubMed Central  Google Scholar 

  23. Viana, F., de la Pena, E., Pecson, B., Schmidt, R. F. & Belmonte, C. Swelling-activated calcium signalling in cultured mouse primary sensory neurons. Eur. J. Neurosci. 13, 722–734 (2001).

    Article  CAS  Google Scholar 

  24. Bevan, S. & Szolcsanyi, J. Sensory neuron–specific actions of capsaicin: mechanisms and applications. Trends Pharmacol. Sci. 11, 330–333 (1990).

    Article  CAS  Google Scholar 

  25. LaMotte, R. H. & Thalhammer, J. G. Response properties of high-threshold cutaneous cold receptors in the primate. Brain Res. 244, 279–287 (1982).

    Article  CAS  Google Scholar 

  26. Schafer, K., Braun, H. A. & Isenberg, C. Effect of menthol on cold receptor activity. Analysis of receptor processes. J. Gen. Physiol. 88, 757–776 (1986).

    Article  CAS  Google Scholar 

  27. Eccles, R. Menthol and related cooling compounds. J. Pharm. Pharmacol. 46, 618–630 (1994).

    Article  CAS  Google Scholar 

  28. Green, B. G. The sensory effects of l-menthol on human skin. Somatosens. Mot. Res. 9, 235–244 (1992).

    Article  CAS  Google Scholar 

  29. Schafer, K., Braun, H. A. & Kurten, L. Analysis of cold and warm receptor activity in vampire bats and mice. Pflugers Arch. 412, 188–194 (1988).

    Article  CAS  Google Scholar 

  30. Braun, H. A., Bade, H. & Hensel, H. Static and dynamic discharge patterns of bursting cold fibers related to hypothetical receptor mechanisms. Pflugers Arch. 386, 1–9 (1980).

    Article  CAS  Google Scholar 

  31. Iggo, A. & Young, D. W. Cutaneous thermoreceptors and thermal nociceptors. in The Somatosensory System (ed. Kornhuber, H. H.) 5–22 (Thieme, Stuttgart, 1975).

    Google Scholar 

  32. Koerber, H. R. & Mendell, L. M. Functional heterogeneity of dorsal root ganglion cells. in Sensory Neurons Diversity, Development, and Plasticity. (ed. Scott, S. A.) 77–96 (Oxford University Press, New York, 1992).

    Google Scholar 

  33. Pape, H. C. Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu. Rev. Physiol. 58, 299–327 (1996).

    Article  CAS  PubMed Central  Google Scholar 

  34. Storm, J. F. Temporal integration by a slowly inactivating K+ current in hippocampal neurons. Nature 336, 379–381 (1988).

    Article  CAS  Google Scholar 

  35. Craig, A. D., Krout, K. & Andrew, D. Quantitative response characteristics of thermoreceptive and nociceptive lamina I spinothalamic neurons in the cat. J. Neurophysiol. 86, 1459–1480 (2001).

    Article  CAS  Google Scholar 

  36. Lesage, F. & Lazdunski, M. Molecular and functional properties of two-pore-domain potassium channels. Am. J. Physiol. Renal Physiol. 279, F793–F801 (2000).

  37. Goldstein, S. A., Bockenhauer, D., O'Kelly, I. & Zilberberg, N. Potassium leak channels and the KCNK family of two-P-domain subunits. Nat. Rev. Neurosci. 2, 175–184 (2001).

    Article  CAS  Google Scholar 

  38. Hervieu, G. J. et al. Distribution and expression of TREK-1, a two-pore-domain potassium channel, in the adult rat CNS. Neuroscience 103, 899–919 (2001).

    Article  CAS  Google Scholar 

  39. Stansfeld, C. E., Marsh, S. J., Halliwell, J. V. & Brown, D.A. 4-Aminopyridine and dendrotoxin induce repetitive firing in rat visceral sensory neurones by blocking a slowly inactivating outward current. Neurosci. Lett. 64, 299–304 (1986).

    Article  CAS  Google Scholar 

  40. Rasband, M. N. et al. Distinct potassium channels on pain-sensing neurons. Proc. Natl. Acad. Sci. USA 98, 13373–13378 (2001).

    Article  CAS  Google Scholar 

  41. Scroggs, R. S., Todorovic, S. M., Anderson, E. G. & Fox, A. P. Variation in IH, IIR, and ILEAK between acutely isolated adult rat dorsal root ganglion neurons of different size. J. Neurophysiol. 71, 271–279 (1994).

    Article  CAS  Google Scholar 

  42. Moosmang, S. et al. Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur. J. Biochem. 268, 1646–1652 (2001).

    Article  CAS  Google Scholar 

  43. Grafe, P., Quasthoff, S., Grosskreutz, J. & Alzheimer, C. Function of the hyperpolarization-activated inward rectification in nonmyelinated peripheral rat and human axons. J. Neurophysiol. 77, 421–426 (1997).

    Article  CAS  Google Scholar 

  44. Takigawa, T., Alzheimer, C., Quasthoff, S. & Grafe, P. A special blocker reveals the presence and function of the hyperpolarization-activated cation current IH in peripheral mammalian nerve fibres. Neuroscience 82, 631–634 (1998).

    Article  CAS  Google Scholar 

  45. Waldmann, R. & Lazdunski, M. H(+)-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels. Curr. Opin. Neurobiol. 8, 418–424 (1998).

    Article  CAS  Google Scholar 

  46. Garcia-Anoveros, J. & Corey, D. P. The molecules of mechanosensation. Annu. Rev. Neurosci. 20, 567–594 (1997).

    Article  CAS  Google Scholar 

  47. Hamill, O. P. & Martinac, B. Molecular basis of mechanotransduction in living cells. Physiol. Rev. 81, 685–740 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank C. Robert for performing the experiment shown in Fig. 1f; R. Velasco, E. Quintero and A. Perez for technical assistance; S. Ingham for illustrations; and M. Domínguez, R. Gallego, F. Moya, M. Sánchez-Vives, R. Schmidt and M. Valdeolmillos for critical comments. This work was supported by funds from the Spanish MICYT (SAF99-0066-C02-01) and FIS (01/1162).

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  1. Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Apartado 18, San Juan de Alicante, 03550, Spain

    Félix Viana, Elvira de la Peña & Carlos Belmonte

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  1. Félix Viana
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Correspondence to Félix Viana.

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Viana, F., de la Peña, E. & Belmonte, C. Specificity of cold thermotransduction is determined by differential ionic channel expression. Nat Neurosci 5, 254–260 (2002). https://doi.org/10.1038/nn809

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