Locus coeruleus-spinal noradrenergic signaling drives sleep deprivation-induced hyperalgesia via astrocytic GAT-3.

Sleep deprivation is a prevalent health problem that amplifies pain and prolongs recovery after tissue injury, yet the neural and astrocytic mechanisms underlying this relationship remain poorly defined. Here, we demonstrate that sleep deprivation activates locus coeruleus noradrenergic neurons and elevates spinal norepinephrine levels. Norepinephrine acts on spinal dorsal horn astrocytes through α1-adrenergic receptors, upregulating the astrocyte-enriched GABA transporter GAT-3. The increase in astrocytic GAT-3 was accompanied by reduced spinal GABA content and enhanced activation of spinoparabrachial projection neurons. Chemogenetic inhibition of spinal-projecting locus coeruleus noradrenergic neurons reduced astrocytic GAT-3 expression, increased spinal GABA content, attenuated acute mechanical hypersensitivity, and shortened the duration of incision-evoked mechanical hypersensitivity. These findings support a model in which LC-spinal noradrenergic signaling regulates astrocytic GAT-3 expression and contributes to sleep deprivation-induced hyperalgesia. This mechanistic framework highlights astrocytic GAT-3 as a potential therapeutic target.