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

A Corrigendum to this article was published on 07 September 2012

This article has been updated

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.

Change history

  • 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.

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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.

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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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