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.

  • Brief Communication
  • Published:

Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin

Nature Chemical Biology volume 8, pages 232–234 (2012)Cite this article

Subjects

Abstract

Neuropathic pain is a debilitating condition for which the development of effective treatments has been limited by an incomplete understanding of its chemical basis. We show by using untargeted metabolomics that sphingomyelin-ceramide metabolism is altered in the dorsal horn of rats with neuropathic pain and that the upregulated, endogenous metabolite N,N-dimethylsphingosine induces mechanical hypersensitivity in vivo. These results demonstrate the utility of metabolomics to implicate unexplored biochemical pathways in disease.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Untargeted metabolomics identifies the dysregulation of sphingomyelin-ceramide metabolism in the ipsilateral dorsal horn during chronic neuropathic pain.
Figure 2: DMS elicits neuropathic pain behavior and cytokine release.

Similar content being viewed by others

References

  1. Torrance, N., Smith, B.H., Bennett, M.I. & Lee, A.J. J. Pain 7, 281–289 (2006).

    Article  Google Scholar 

  2. Warfield, C.A. & Fausett, H.J. Manual of pain management. in Manual of Pain Management (eds. Warfield, C.A. & Fausett, H.J.) 193–199 (Lippincott Williams & Wilkins, 2002).

  3. Woolf, C.J. & Mannion, R.J. Lancet 353, 1959–1964 (1999).

    Article  CAS  Google Scholar 

  4. Singh, O.V. et al. Proteomics 9, 1241–1253 (2009).

    Article  CAS  Google Scholar 

  5. Sung, Y.J. & Ambron, R.T. Neurol. Res. 26, 195–203 (2004).

    Article  CAS  Google Scholar 

  6. Hofmann, H.A., De Vry, J., Siegling, A., Spreyer, P. & Denzer, D. Eur. J. Pharmacol. 470, 17–25 (2003).

    Article  CAS  Google Scholar 

  7. Hannun, Y.A. & Obeid, L.M. Nat. Rev. Mol. Cell Biol. 9, 139–150 (2008).

    Article  CAS  Google Scholar 

  8. Ogretmen, B. & Hannun, Y.A. Nat. Rev. Cancer 4, 604–616 (2004).

    Article  CAS  Google Scholar 

  9. Latorre, E., Aragones, M.D., Fernandez, I. & Catalan, R.E. Eur. J. Biochem. 262, 308–314 (1999).

    Article  CAS  Google Scholar 

  10. Göggel, R. et al. Nat. Med. 10, 155–160 (2004).

    Article  Google Scholar 

  11. Woolf, C.J., Shortland, P. & Coggeshall, R.E. Nature 355, 75–78 (1992).

    Article  CAS  Google Scholar 

  12. Knyihár-Csillik, E., Rakic, P. & Csillik, B. Cell Tissue Res. 247, 599–604 (1987).

    Article  Google Scholar 

  13. Inoue, M. et al. Nat. Med. 10, 712–718 (2004).

    Article  CAS  Google Scholar 

  14. Igarashi, Y. et al. J. Biol. Chem. 265, 5385–5389 (1990).

    CAS  PubMed  Google Scholar 

  15. Lee, Y.K., Kim, H.L., Kim, Y.L. & Im, D.S. Mol. Cells 23, 11–16 (2007).

    CAS  PubMed  Google Scholar 

  16. Nie, H. & Weng, H.R. J. Neurophysiol. 103, 2570–2580 (2010).

    Article  CAS  Google Scholar 

  17. Scholz, J. & Woolf, C.J. Nat. Neurosci. 10, 1361–1368 (2007).

    Article  CAS  Google Scholar 

  18. Watkins, L.R., Milligan, E.D. & Maier, S.F. Trends Neurosci. 24, 450–455 (2001).

    Article  CAS  Google Scholar 

  19. Alexander, G.M., van Rijn, M.A., van Hilten, J.J., Perreault, M.J. & Schwartzman, R.J. Pain 116, 213–219 (2005).

    Article  CAS  Google Scholar 

  20. Wolf, G., Gabay, E., Tal, M., Yirmiya, R. & Shavit, Y. Pain 120, 315–324 (2006).

    Article  CAS  Google Scholar 

  21. Gao, Y.J. et al. J. Neurosci. 29, 4096–4108 (2009).

    Article  CAS  Google Scholar 

  22. Coste, O. et al. J. Biol. Chem. 283, 32442–32451 (2008).

    Article  CAS  Google Scholar 

  23. Edsall, L.C., Van Brocklyn, J.R., Cuvillier, O., Kleuser, B. & Spiegel, S.N. Biochemistry 37, 12892–12898 (1998).

    Article  CAS  Google Scholar 

  24. Morales, P.R. et al. Drug Chem. Toxicol. 30, 197–216 (2007).

    Article  CAS  Google Scholar 

  25. Igarashi, Y. & Hakomori, S. Biochem. Biophys. Res. Commun. 164, 1411–1416 (1989).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the US National Institutes of Health (NIH) R24 EY017540-04 (G.S.), P30 MH062261 (M.M., G.S.) and P01 DA026146-02 (G.S.) in addition to RR025774 (M.M.); NIH–National Institute of Aging L30 AG0 038036 (G.J.P.); and NIH–National Institute of Neurological Disorders and Stroke F32NS068015 and T32 NSO41219 (L.P.S.). We also acknowledge financial support from the US Department of Energy FG02-07ER64325 and DE-AC0205CH11231).

Author information

Author notes

  1. Jean-Phillipe Courade

    Present address: Current address: UCB Pharma, Chemin du Foriest, Braine-L'Alleud, Belgium.,

Authors and Affiliations

  1. Department of Chemistry, Washington University School of Medicine, St. Louis, Missouri, USA

    Gary J. Patti

  2. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA

    Gary J. Patti

  3. Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

    Gary J. Patti

  4. Department of Chemistry, Scripps Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, La Jolla, California, USA

    Oscar Yanes, Ralf Tautenhahn & Gary Siuzdak

  5. Department of Molecular Biology, Scripps Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, La Jolla, California, USA

    Oscar Yanes, Ralf Tautenhahn & Gary Siuzdak

  6. The Metabolomics Platform of the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Rovira i Virgili University, Taragona, Spain

    Oscar Yanes

  7. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California–San Diego, La Jolla, California, USA

    Leah P Shriver & Marianne Manchester

  8. Pain Research Unit, Pfizer Global Research and Development, Kent, UK

    Jean-Phillipe Courade

Authors
  1. Gary J. Patti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oscar Yanes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leah P Shriver
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean-Phillipe Courade
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ralf Tautenhahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marianne Manchester
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gary Siuzdak
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.J.P. and O.Y. contributed equally to this work. G.J.P., L.P.S. and J.C. performed work on rats. G.J.P., O.Y. and L.P.S. performed analytical experiments. G.J.P., O.Y., L.P.S., J.-P.C., R.T., M.M. and G.S. contributed to experimental design, performed data analysis and wrote the manuscript.

Corresponding authors

Correspondence to Marianne Manchester or Gary Siuzdak.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods and Supplementary Results (PDF 4511 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Patti, G., Yanes, O., Shriver, L. et al. Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin. Nat Chem Biol 8, 232–234 (2012). https://doi.org/10.1038/nchembio.767

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.767

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research