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Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy

Nature Medicine volume 18, pages 926–933 (2012)Cite this article

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A Corrigendum to this article was published on 07 September 2012

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Abstract

This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Nav1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Nav1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Nav1.8 knockout (Scn10−/−) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal- and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy.

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Figure 1: Methylglyoxal and pain in individuals with diabetes.
Figure 2: Exogenous methylglyoxal (MG) and STZ-induced diabetes induce thermal hyperalgesia.
Figure 3: Overexpressing GLO1 or scavenging methylglyoxal by a synthetic peptide reduces thermal hyperalgesia in methylglyoxal-treated and diabetic mice.
Figure 4: Methylglyoxal requires Nav1.8 to induce hyperexcitability and thermal hyperalgesia.
Figure 5: Methylglyoxal causes a cascade of neurochemical changes and activates brain regions involved in pain processing.
Figure 6: Effects of methylglyoxal on action potential generation and Na+ currents in sensory neurons.

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  • 06 July 2012

     In the version of this article initially published, in Figure 1a, the bar for 3-deoxyglucosone was incorrectly labeled as 3-diacylglycerol. In Figure 6b, the labels for the control and methylglyoxal-treated samples were incorrectly switched. Also, Felix Lasitschka’s last name was misspelled as Lasischka. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors thank S. Kaymak for immunohistochemistry, A. Buhl and K. Leotta for assistance in the cerebral blood flow experiments, L. Werner for support with bregma gradings and X. Du and A. Erhardt for the daily care of the mice. A. Bierhaus, J.F., M.E.C., M.B. and P.P.N. were supported by a Centre grant from the Juvenile Diabetes Research Foundation (JDRF). This work was also supported in part by grants from the Deutsche Forschungsgemeinschaft (BI-1281/3-1 to A. Bierhaus; LU728/3-1 and NA-350/3-2 in KFO 130 to P.W.R., C. Nau and A.L.), the US National Institutes of Health (2R56DK33861-21 to M.B.), the European Foundation for the Study of Diabetes (EFSD/Lilly-Programme, to A. Bierhaus), the German Diabetes Association (DDG, Christian-Hagedorn-Award to A. Bierhaus), the Manfred-Lautenschläger-Stiftung for Diabetes (LSD, to P.P.N.), the Dietmar-Hopp-Stiftung (to A. Bierhaus, P.M.H. and P.P.N.) and the Network Aging Research (NAR, to A. Bierhaus). A. Babes and C.N. were supported by grant PN2 164/2007 from the Romanian Research Council (CNCSIS). A. Babes also received support from the Alexander von Humboldt Foundation.

Author information

Author notes

  1. Angelika Bierhaus, Thomas Fleming and Michael Brownlee: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany

    Angelika Bierhaus, Thomas Fleming, Stoyan Stoyanov, Ilze Konrade, Ivan K Lukic, Michael Morcos, Per M Humpert & Peter P Nawroth

  2. Department of Anesthesiology and Intensive Care, Hannover Medical School, Hannover, Germany

    Andreas Leffler

  3. Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

    Andreas Leffler & Carla Nau

  4. Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

    Alexandru Babes, Susanne K Sauer, Mirjam Eberhardt, Winfried L Neuhuber, Tatjana I Kichko & Peter W Reeh

  5. Department of Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania

    Alexandru Babes & Cristian Neacsu

  6. Functional Proteome Analysis B100, Core Facility Protein Analysis W120, German Cancer Research Center, Heidelberg, Germany

    Martina Schnölzer

  7. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    Felix Lasitschka

  8. Stradins University, Riga Eastern Clinical University Hospital, Riga, Latvia

    Ilze Konrade

  9. Sanofi-Aventis Deutschland, Frankfurt, Germany

    Ralf Elvert

  10. Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany

    Walter Mier & Uwe Haberkorn

  11. University of Latvia, Pauls Stradins Clinical University Hospital, Riga, Latvia

    Valdis Pirags

  12. Biosistemi d.o.o., Zagreb, Croatia

    Ivan K Lukic

  13. Zentrum für Psychiatrie Südwürttemberg, Zwiefalten, Germany

    Thomas Dehmer

  14. Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, University Hospital, Coventry, UK

    Naila Rabbani & Paul J Thornalley

  15. Albert Einstein College of Medicine, Bronx, New York, USA

    Diane Edelstein & Michael Brownlee

  16. Baker International Diabetes Institute, Heart and Diabetes Institute, Melbourne, Victoria, Australia

    Josephine Forbes & Mark E Cooper

  17. Institute for Experimental und Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany

    Markus Schwaninger

  18. Institute for Clinical Diabetology, German Diabetes Center at the Heinrich Heine University Leibniz Center For Diabetes Research, Düsseldorf, Germany

    Dan Ziegler

  19. University of Tennessee College of Medicine, Memphis, Tennessee, USA

    David M Stern

Authors
  1. Angelika Bierhaus
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Contributions

A. Bierhaus planned, performed and supervised all experiments, was responsible for the data interpretation and wrote the manuscript. T.F. and S.S. performed most of the mouse experiments, and T.F. also did the biochemical analytics and cell culture experiments. A.L. and C. Nau performed the voltage clamp studies and were involved in data interpretation. A. Babes and C. Neacsu performed the current clamp studies and were involved in data interpretation. S.K.S., M.E. and T.I.K. performed CGRP-release experiments and single-fiber recordings in the skin-nerve preparation and were involved in data interpretation. M. Schnölzer, N.R. and P.J.T. were involved in the dicarbonyl analytics and data interpretation. F.L. provided biopsies of human sciatic nerves. W.L.N. performed electron microscopy. R.E. and I.K.L. performed the nerve conduction velocity experiments and the measurements of tactile allodynia. W.M., M. Schwaninger and U.H. supervised the cerebral blood flow measurements and were involved in data interpretation. T.D. was involved in the isolation and characterization of the DRG. D.E. generated the Glo1−/+ mice. J.F. and M.E.C. provided ALT-711 and were involved in data interpretation. I.K., V.P. and M.M. performed the clinical studies. P.M.H. supervised the clinical studies and was involved in data interpretation. D.M.S. was involved in data interpretation and the writing of the manuscript. D.Z. provided the human skin biopsies and was involved in data interpretation. M.B. provided the Glo1−/+ mice and was involved in data interpretation and the writing of the manuscript. P.W.R. supervised the electrophysiological part of the project and wrote the manuscript. P.P.N. supervised the project and wrote the manuscript. Senior coauthorship is shared by P.W.R. and P.P.N.

Corresponding author

Correspondence to Peter P Nawroth.

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Bierhaus, A., Fleming, T., Stoyanov, S. et al. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 18, 926–933 (2012). https://doi.org/10.1038/nm.2750

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