Abstract
Neuropathic pain is pervasive among people with diabetes. The integrated stress response (ISR) is a key mechanism of translational regulation implicated in diabetic pain. In this study, we demonstrate that a reactive glycolytic metabolite, methylglyoxal (MGO), which is strongly associated with painful diabetic neuropathy, activates the ISR through the kinase general control nonderepressible 2 (GCN2). Methylglyoxal disrupts elongating ribosomes, triggering the recruitment of ribosome quality control factors and collision sensors. GCN2 activation by MGO requires the ribosomal P-stalk, a critical sensor for elongation factors. Moreover, neuronal sensitization and mechanical allodynia produced by MGO are GCN2-dependent. Overall, this study links ribosomal elongation dysfunction to metabolic pain and identifies GCN2 as a novel analgesic target for diabetic neuropathy.