What Do We Know About Pain Pathways in Diabetic Peripheral Neuropathy? A Contemporary Narrative Review.

PURPOSE: Diabetic peripheral neuropathy (DPN) affects up to 50% of individuals with diabetes mellitus and remains one of the most prevalent and disabling chronic complications of the disease. Approximately one-third develop painful DPN (pDPN), characterized by spontaneous burning pain, electric-shock sensations, allodynia, and hyperalgesia, all of which significantly impair quality of life. Classical mechanisms, including hyperglycemia-driven oxidative stress, mitochondrial dysfunction, microvascular insufficiency, ion-channel dysregulation, and neuroinflammatory activation, explain the structural and functional deterioration of peripheral nerves but do not fully account for the emergence of painful phenotypes. In this narrative review, we aim to provide an overview of the current understanding of pDPN, focusing on how peripheral metabolic and neuroimmune disturbances interact with central nervous system plasticity to produce chronic pain, and highlight emerging evidence that mechanistic endotypes may guide more precise, individualized therapies. METHODS: Comprehensive electronic databases, including PubMed and Web of Science, were searched to identify peer-reviewed experimental and clinical studies published in English that addressed the pathophysiological mechanisms underlying pDPN. The literature search focused on studies investigating peripheral metabolic and neuroimmune disturbances, as well as central nervous system plasticity relevant to chronic pain. Particular emphasis was placed on emerging molecular pathways implicated in nociceptor sensitization and pain signaling, including neuroinflammatory, synaptic, and intracellular signaling mechanisms. FINDINGS: Recent advances in molecular neuroscience have identified several biological pathways that contribute specifically to pain generation, including inflammatory signaling, altered synaptic plasticity, intracellular kinase activation, mitochondrial dysfunction, and Schwann cell injury. These mechanisms promote nociceptor sensitization and contribute to the development and maintenance of chronic neuropathic pain. IMPLICATIONS: By highlighting these mechanisms, this review emphasizes how metabolic and neuroimmune disturbances interact with central nervous system plasticity to produce chronic pain and suggests that emerging mechanistic endotypes may guide more precise, individualized therapy.