Methylglyoxal modification of Na v 1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy

Bierhaus, Angelika, Fleming, Thomas, Stoyanov, Stoyan, Leffler, Andreas, Babes, Alexandru, Neacsu, Cristian, Sauer, Susanne K., Eberhardt, Mirjam, Schnoelzer, Martina, Lasischka, Felix, Neuhuber, Winfried L., Kichko, Tatjana I., Konrade, Ilze, Elvert, Ralf, Mier, Walter, Pirags, Valdis, Lukic, Ivan K., Morcos, Michael, Dehmer, Thomas, Rabbani, Naila, Thornalley, Paul J., Edelstein, Diane, Nau, Carla, Forbes, Josephine, Humpert, Per M., Schwaninger, Markus, Ziegler, Dan, Stern, David M., Cooper, Mark E., Haberkorn, Uwe, Brownlee, Michael, Reeh, Peter W. and Nawroth, Peter P. (2012) Methylglyoxal modification of Na v 1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nature Medicine, 18 6: 926-933. doi:10.1038/nm.2750


Author Bierhaus, Angelika
Fleming, Thomas
Stoyanov, Stoyan
Leffler, Andreas
Babes, Alexandru
Neacsu, Cristian
Sauer, Susanne K.
Eberhardt, Mirjam
Schnoelzer, Martina
Lasischka, Felix
Neuhuber, Winfried L.
Kichko, Tatjana I.
Konrade, Ilze
Elvert, Ralf
Mier, Walter
Pirags, Valdis
Lukic, Ivan K.
Morcos, Michael
Dehmer, Thomas
Rabbani, Naila
Thornalley, Paul J.
Edelstein, Diane
Nau, Carla
Forbes, Josephine
Humpert, Per M.
Schwaninger, Markus
Ziegler, Dan
Stern, David M.
Cooper, Mark E.
Haberkorn, Uwe
Brownlee, Michael
Reeh, Peter W.
Nawroth, Peter P.
Title Methylglyoxal modification of Na v 1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy
Formatted title
Methylglyoxal modification of Nav 1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy
Journal name Nature Medicine   Check publisher's open access policy
ISSN 1078-8956
1546-170X
Publication date 2012-06-01
Year available 2012
Sub-type Article (original research)
DOI 10.1038/nm.2750
Open Access Status Not yet assessed
Volume 18
Issue 6
Start page 926
End page 933
Total pages 8
Place of publication New York, United States
Publisher Nature Publishing Group
Language eng
Formatted 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.
Keyword Diabetes
Ion channels
Neuropathic pain
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID BI-1281/3-1
2R56DK33861-21
PN2 164/2007
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
School of Medicine Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 194 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 201 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Mon, 15 Dec 2014, 20:47:39 EST by System User on behalf of Learning and Research Services (UQ Library)