Descending locus coeruleus noradrenergic signaling to spinal astrocyte subset is required for stress-induced mechanical pain hypersensitivity

It is known that stress powerfully alters pain, but its underlying mechanisms remain elusive. Here, we identified a circuit, locus coeruleus descending noradrenergic neurons projecting to the spinal dorsal horn (LC^→SDH-NA neurons), that is activated by acute exposure to restraint stress and is required for stress-induced mechanical pain hypersensitivity in mice. Interestingly, the primary target of spinal NA released from descending LC^→SDH-NAergic terminals causing the stress-induced pain hypersensitivity was α_1A-adrenaline receptors (α_1ARs) in Hes5-positive (Hes5⁺) astrocytes located in the SDH, an astrocyte subset that has an ability to induce pain sensitization. Furthermore, activation of Hes5⁺ astrocytes reduced activity of SDH-inhibitory neurons (SDH-INs) that have an inhibitory role in pain processing. This astrocytic reduction of IN activity was canceled by an A₁-adenosine receptor (A₁R)-knockdown in SDH-INs, and the A₁R-knockdown suppressed pain hypersensitivity caused by acute restraint stress. Therefore, our findings suggest that LC^→SDH-NA neuronal signaling to Hes5⁺ SDH astrocytes and subsequent astrocytic reduction of SDH-IN activity are essential for mechanical pain facilitation caused by stress.