title: Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy.
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 Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. 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 Na(v)1.8 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.
authors.affiliation: Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleming
authors.forename: Stoyan
authors.initials: S
authors.lastname: Stoyanov
authors.forename: Andreas
authors.initials: A
authors.lastname: Leffler
authors.forename: Alexandru
authors.initials: A
authors.lastname: Babes
authors.forename: Cristian
authors.initials: C
authors.lastname: Neacsu
authors.forename: Susanne K
authors.initials: SK
authors.lastname: Sauer
authors.forename: Mirjam
authors.initials: M
authors.lastname: Eberhardt
authors.forename: Martina
authors.initials: M
authors.lastname: Schnölzer
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.forename: Felix
authors.initials: F
authors.lastname: Lasischka
authors.forename: Winfried L
authors.initials: WL
authors.lastname: Neuhuber
authors.forename: Tatjana I
authors.initials: TI
authors.lastname: Kichko
authors.forename: Ilze
authors.initials: I
authors.lastname: Konrade
authors.forename: Ralf
authors.initials: R
authors.lastname: Elvert
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
authors.forename: Valdis
authors.initials: V
authors.lastname: Pirags
authors.forename: Ivan K
authors.initials: IK
authors.lastname: Lukic
authors.forename: Michael
authors.initials: M
authors.lastname: Morcos
authors.forename: Thomas
authors.initials: T
authors.lastname: Dehmer
authors.forename: Naila
authors.initials: N
authors.lastname: Rabbani
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thornalley
authors.forename: Diane
authors.initials: D
authors.lastname: Edelstein
authors.forename: Carla
authors.initials: C
authors.lastname: Nau
authors.forename: Josephine
authors.initials: J
authors.lastname: Forbes
authors.forename: Per M
authors.initials: PM
authors.lastname: Humpert
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
authors.forename: Dan
authors.initials: D
authors.lastname: Ziegler
authors.forename: David M
authors.initials: DM
authors.lastname: Stern
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.forename: Peter W
authors.initials: PW
authors.lastname: Reeh
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
mesh_terms: D000818:Animals; D002560:Cerebrovascular Circulation; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009431:Neural Conduction / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology; D011765:Pyruvaldehyde / Q000494:pharmacology*; D015222:Sodium Channels / Q000502:physiology*; D013311:Streptozocin; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C568318:Scn10a protein, mouse; D015222:Sodium Channels; D013779:Tetrodotoxin; D013311:Streptozocin; D011765:Pyruvaldehyde