Schematic illustration of local and remote central sensitization induced by glial activation and neuroinflammation in the spinal cord. Activation of spinal microglia and astrocytes by painful insults results in secretion of glial mediators such as tumor necrosis factor (TNF), interleukin (IL)-1β, chemokine (CC motif) ligand 2 (CCL2), chemokine (CXC motif) ligand 1 (CXCL1), brain-derived neurotrophic factor (BDNF), and d-serine, which can act as neuromodulators to induce local central sensitization in surrounding excitatory synapses (facilitation) and inhibitory synapses (disinhibition). During neuroinflammation, these glial mediators also affect synapses in different spinal segments to cause remote central sensitization and extraterritorial and widespread pain beyond the initial injury site. It is also possible that central sensitization may further promote peripheral sensitization via neuroinflammation. AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CSF = cerebrospinal fluid; GABA = γ-aminobutyric acid; GABAR = γ-aminobutyric acid receptor; Glu = glutamate; GlyR = glycine receptor; NMDAR = N-methyl-d-aspartate receptor.