Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons

Abstract

PAIN is normally evoked only by stimuli that are sufficiently intense to activate high-threshold Aδ and C sensory fibres, which relay the signal to the spinal cord. Peripheral inflammation leads to profoundly increased pain sensitivity: noxious stimuli generate a greater response and stimuli that are normally innocuous elicit pain. Inflammation increases the sensitivity of the peripheral terminals of Aδ and C fibres at the site of inflammation1. It also increases the excitability of spinal cord neurons2,3, which now amplify all sensory inputs including the normally innocuous tactile stimuli that are conveyed by low-threshold Aβ fibres. This central sensitization has been attributed to the enhanced activity of C fibres4, which increase the excitability of their postsynaptic targets by releasing glutamate and the neuropeptide substance P5–7. Here we show that inflammation results in Aβ fibres also acquiring the capacity to increase the excitability of spinal cord neurons. This is due to a phenotypic switch in a subpopulation of these fibres so that they, like C-fibres, now express substance P. Aβ fibres thus appear to contribute to inflammatory hypersensitivity by switching their phenotype to one resembling pain fibres, thereby enhancing synaptic transmission in the spinal cord and exaggerating the central response to innocuous stimuli.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Reeh, P. W. in Cellular Mechanisms of Sensory Processing: Cell Biology Vol. 79 (ed. Urban, L.) Vol. 1st, 119–131 (Springer, Berlin, 1994).

    Book  Google Scholar 

  2. Woolf, C. J. Nature 306, 686–688 (1983).

    Article  ADS  CAS  Google Scholar 

  3. Torebjork, H. E., Lundberg, L. E. R. & LaMotte, R. H. J. Physiol. (Lond.) 448, 765–780 (1992).

    Article  CAS  Google Scholar 

  4. Woolf, C. J. & Wall, P. D. J. Neurosci. 6, 1433–1443 (1986).

    Article  CAS  Google Scholar 

  5. Woolf, C. J. & Thompson, S. W. N. Pain 44, 293–299 (1991).

    Article  CAS  Google Scholar 

  6. Xu, X.-J., Dalsgaard, C.-J. & Wiesenfeld-Hallin, Z. Eur. J. Pharmacol. 216, 337–344 (1992).

    Article  CAS  Google Scholar 

  7. Ma, Q.-P. & Woolf, C. J. J. Physiol. (Lond.) 486.3, 769–777 (1995).

    Article  Google Scholar 

  8. Averill, S., McMahon, S. B., Clary, D. O., Reichardt, L. F. & Priestley, J. V. Eur. J. Neurosci. 7, 1484–1494 (1995).

    Article  CAS  Google Scholar 

  9. Fitzgerald, M., Wall, P. D., Goedert, M. & Emson, P. C. Brain Res. 332, 131–141 (1985).

    Article  CAS  Google Scholar 

  10. Verge, V. M. K., Richardson, P. M., Wiesenfeld-Hallin, Z. & Hokfelt, T. J. Neurosci. 15, 2081–2096 (1995).

    Article  CAS  Google Scholar 

  11. Noguchi, K., Kawai, Y., Fukuoka, T., Senba, E. & Miki, K. J. Neurosci. 15, 7633–7643 (1995).

    Article  CAS  Google Scholar 

  12. Woolf, C. J., Safieh-Garabedian, B., Ma, Q.-P, Crilly, P. & Winter, J. Neuroscience 62, 327–331 (1994).

    Article  CAS  Google Scholar 

  13. Leslie, T. A., Emson, P. C., Dowd, P. M. & Woolf, C. J. Neuroscience 67, 753–761 (1995).

    Article  CAS  Google Scholar 

  14. Donnerer, J., Schuligoi, R. & Stein, C. Neuroscience 49, 693–698 (1992).

    Article  CAS  Google Scholar 

  15. Lewin, G. R., Rueff, A. & Mendell, L. M. Eur. J. Neurosci. 6, 1903–1912 (1994).

    Article  CAS  Google Scholar 

  16. McMahon, S. B., Bennett, D. L. H., Priestley, J. V. & Shelton, D. L. Nature Med. 1, 774–780 (1995).

    Article  CAS  Google Scholar 

  17. Ma, Q.-P. & Woolf, C. J. Pain 67, 97–106 (1996).

    Article  CAS  Google Scholar 

  18. Robertson, B., Perry, M. J. & Lawson, S. N. J. Neurocytol. 20, 387–395 (1991).

    Article  CAS  Google Scholar 

  19. Warden, M. K. & Young, W. S. J. Comp. Neurol. 272, 90–113 (1988).

    Article  CAS  Google Scholar 

  20. Thompson, S. W. N., King, A. E. & Woolf, C. J. Eur.J. Neurosci. 2, 638–649 (1990).

    Article  CAS  Google Scholar 

  21. Urban, L. & Randic, M. Brain Res. 291, 336–341 (1984).

    Article  Google Scholar 

  22. Heath, M. J., Womack, M. D. & MacDermott, A. B. J. Neurophysiol. 72, 1192–1198 (1994).

    Article  CAS  Google Scholar 

  23. Chen, L. & Huang, L.-Y. M. Nature 356, 521–523 (1992).

    Article  ADS  CAS  Google Scholar 

  24. Woolf, C. J. & King, A. E. J. Neurosci. 10, 2717–2726 (1990).

    Article  CAS  Google Scholar 

  25. Thompson, S. W. N., Dray, A. & Urban, L. J. Neurosci. 14, 3672–3687 (1994).

    Article  CAS  Google Scholar 

  26. Woolf, C. J. J. Comp. Neurol. 261, 105–119 (1987).

    Article  CAS  Google Scholar 

  27. Mantyh, P. W. et al. Science 268, 1629–1632 (1995).

    Article  ADS  CAS  Google Scholar 

  28. Woolf, C. J., Shortland, P. & Sivilotti, L. G. Pain 58, 141–155 (1994).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Neumann, S., Doubell, T., Leslie, T. et al. Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons. Nature 384, 360–364 (1996). https://doi.org/10.1038/384360a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/384360a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing