Activation of spinal dorsal horn astrocytes by noxious stimuli involves descending noradrenergic signaling

Astrocytes are critical regulators of neuronal function in the central nervous system (CNS). We have previously shown that astrocytes in the spinal dorsal horn (SDH) have increased intracellular Ca²⁺ levels following intraplantar injection of the noxious irritant, formalin. However, the underlying mechanisms remain unknown. We investigated these mechanisms by focusing on the role of descending noradrenergic (NAergic) signaling because our recent study revealed the essential role of the astrocytic Ca²⁺ responses evoked by intraplantar capsaicin. Using in vivo SDH imaging, we found that the Ca²⁺ level increase in SDH astrocytes induced by intraplantar formalin injection was suppressed by ablation of SDH-projecting locus coeruleus (LC)-NAergic neurons. Furthermore, the formalin-induced Ca²⁺ response was dramatically decreased by the loss of α_1A-adrenaline receptors (ARs) in astrocytes located in the superficial laminae of the SDH. Moreover, similar inhibition was observed in mice pretreated intrathecally with an α_1A-AR-specific antagonist. Therefore, activation of α_1A-ARs via descending LC-NAergic signals may be a common mechanism underlying astrocytic Ca²⁺ responses in the SDH evoked by noxious stimuli, including chemical irritants.