Spinal astrocytes in superficial laminae gate brainstem descending control of mechanosensory hypersensitivity

Kohro et al. identify a population of astrocytes located in the superficial dorsal horn of adult spinal cord (genetically defined byHes5) that acts as a gate for locus coeruleus descending noradrenergic control of mechanosensory hypersensitivity. Astrocytes are critical regulators of CNS function and are proposed to be heterogeneous in the developing brain and spinal cord. Here we identify a population of astrocytes located in the superficial laminae of the spinal dorsal horn (SDH) in adults that is genetically defined byHes5. In vivo imaging revealed that noxious stimulation by intraplantar capsaicin injection activatedHes5(+)SDH astrocytes via alpha(1A)-adrenoceptors (alpha(1A)-ARs) through descending noradrenergic signaling from the locus coeruleus. Intrathecal norepinephrine induced mechanical pain hypersensitivity via alpha(1A)-ARs inHes5(+)astrocytes, and chemogenetic stimulation ofHes5(+)SDH astrocytes was sufficient to produce the hypersensitivity. Furthermore, capsaicin-induced mechanical hypersensitivity was prevented by the inhibition of descending locus coeruleus-noradrenergic signaling ontoHes5(+)astrocytes. Moreover, in a model of chronic pain, alpha(1A)-ARs inHes5(+)astrocytes were critical regulators for determining an analgesic effect of duloxetine. Our findings identify a superficial SDH-selective astrocyte population that gates descending noradrenergic control of mechanosensory behavior.