Diabetic neuropathic pain (DNP) is a common and debilitating complication of diabetes that profoundly reduces patient quality of life. Despite extensive research, current treatments remain largely sym Show more
Diabetic neuropathic pain (DNP) is a common and debilitating complication of diabetes that profoundly reduces patient quality of life. Despite extensive research, current treatments remain largely symptomatic, with limited efficacy and significant side effects. Microglia act as pivotal mediators of DNP through RAGE/TLR4/NLRP3-driven IL-1β and BDNF release that amplifies spinal pain signaling. Microglia respond directly to hyperglycemia-induced cues such as advanced glycation end-products, reactive oxygen species, ATP, and pro-inflammatory signals, becoming activated and releasing cytokines, chemokines, and neuromodulators including BDNF that amplify spinal pain signaling. This review synthesizes recent insights into the molecular triggers of microglial activation such as RAGE, TLRs, purinergic receptors, and inflammasomes and the downstream intracellular pathways including NF-κB, MAPK, PI3K/Akt, and BDNF-TrkB that drive neuroinflammation. We further examine neuroimmune crosstalk, including bidirectional microglia-neuron and microglia-astrocyte signaling, which sustains central sensitization. Translational studies linking these pathways to human DNP are evaluated, along with novel technologies that illuminate microglial phenotypes. Emerging therapeutic strategies focus on inhibition of these pathways, including RAGE antagonists and purinergic receptor blockers. However, a critical translational gap persists owing to insufficient human validation of microglial biomarkers and the limited fidelity of current animal models. By integrating basic and clinical findings, we underscore the promise of microglia-focused interventions to complement traditional analgesics and ultimately improve outcomes in DNP patients. Show less