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Diabetic neuropathic pain (DNP) is a debilitating condition. Current therapies are
ineffective at treating DNP. We have previously demonstrated that methylglyoxal (MGO),
a reactive metabolite of glycolysis that is elevated in the plasma of diabetic patients,
pain hypersensitivity by engaging the integrated stress response (ISR) in mice. Induction
of the ISR alters protein synthesis by inhibiting eukaryotic initiation factor 2α
(eIF2α) and relying on eIF2A-mediated translation. We hypothesize that eIF2A regulates
protein synthesis that contributes to pain hypersensitivity under conditions of ISR,
especially after MGO application. We employed the recently characterized eIF2A-/-
mouse to investigate how MGO treatment induces the ISR, facilitates eIF2A-mediated
translation, and consequently causes pain hypersensitivity. We also subjected mice
to tunicamycin (TUN), a well-known ISR inducer, and spared nerve injury (SNI). With
donated human dorsal root ganglia (DRG) and spinal nerves (SpN), we aimed to translate
our finding in rodents to humans. Intraplantar and intraperitoneal administrations
of MGO induced pain hypersensitivity in a dose-dependent manner in male and female
WT animals but not in eIF2A-/- mice. Following TUN and SNI, the eIF2A-/-¬¬ mice were
protected against ISR-dependent pain (tunicamycin) but not against ISR-independent
pain (SNI). MGO treatment of human DRG and SpN explants, and cultured human DRG neurons
elevated p-eIF2α and eIF2A levels suggesting that MGO induces ISR not only in mice,
but also in humans. Carboxyethyl lysine (CEL), a byproduct of reactive MGO and lysine
residues, is increased in MGO treated cells and DRG and spinal nerve explants but
not in tunicamycin treated explants, despite sharing elevated p-eIF2α and eIF2A levels.
We demonstrate that eIF2A is necessary for the development of ISR-induced pain hypersensitivity.
We further suggest that MGO and its byproduct, CEL, can be used as a biomarker to
stratify DNP patients that would respond to ISR inhibitors like ISRIB.
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© 2022 Published by Elsevier Inc.