Fig. 3
Central Sensitization Model Induced by the Neurotoxic Triad. (1) Excessive glutamate release and reduced reuptake of glutamate by astrocytes (through EAAT) leads to excitotoxicity, triggering massive Ca2+ influx in second-order neurons, mainly through NMDA receptors. (2) This eventually leads to the production of ROS by mitochondria. (3) ROS enhances NMDA receptor phosphorylation, driving central sensitization. (4) High levels of ROS surpass the cell’s antioxidant capacity causing oxidative stress in second-order neurons. (5) Available glutamate in the synaptic cleft can activate its NMDA and mGlu receptors on nearby microglial cells. (6) In response, microglial cells release inflammatory mediators that increase glutamate release presynaptically, enhance NMDA and AMPA receptor activity postsynaptically (through phosphorylation), and suppress inhibitory GABA and glycine signaling, further amplifying sensitization. These interconnected events form a triad of excitotoxicity, oxidative stress, and neuroinflammation, which not only potentiate central sensitization but also sustain it. NMDA: N-methyl-D-aspartic acid, AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, mGluRs: Metabotropic glutamate receptors, EAAT: Excitatory amino acid transporters, ROS: Reactive oxygen species. Ca2+: calcium, GABA: gamma-aminobutyric acid. Created in https://BioRender.com