Spinal glial remodeling: a critical driver of inhibitory circuit deterioration and central sensitization in...

Peripheral inflammation triggers maladaptive remodeling of spinal inhibitory circuits, which sustains persistent pain hypersensitivity long after initial tissue injury resolves. Although glial activation is well recognized as a key driver of inflammatory pain, the sequential glial-mediated mechanisms that disrupt dorsal horn inhibitory synaptic function remain incompletely summarized. This review examines how sequential microglial and astrocyte activation dismantles inhibitory synaptic control in the dorsal horn during inflammatory pain. Activated microglia release interleukin-1 alpha, tumor necrosis factor-alpha and complement component 1q, which polarize dorsal horn astrocytes to the neurotoxic A1 reactive phenotype, a process that persists for days 3-7 after the acute microglial phase of peripheral inflammation. Brain-derived neurotrophic factor and TrkB signaling mediated by A1 astrocytes leads to downregulation of potassium-chloride cotransporter 2, which causes collapse of the chloride gradient required for gamma-aminobutyric acid and glycine receptor-mediated inhibition. This inhibitory deficit is exacerbated by the prostaglandin E2 (PGE2)-dependent phosphorylation of alpha-3 glycine receptor subunits, epigenetic silencing of glutamic acid decarboxylase 65 (GAD65), and chloride-instability-driven silencing of parvalbumin (PV)-positive interneurons. This descending serotonergic input is responsible for maintaining this glial loop through a spinal serotonin receptor type-3 and a neuron-microglia-astrocyte cascade. Furthermore, we discuss targeted pharmacological strategies, including potassium-chloride cotransporter 2 activators, gamma-aminobutyric acid receptor ligands, glutamate transporter upregulators, connexin-43 mimetic peptides, and serotonin receptor type-3 antagonists. This glia-dependent inhibitory circuit dysfunction represents a promising multi-mechanistic neurotherapeutic target for novel analgesic interventions.