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(1A)Rs) 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 A(1)-adenosine receptor (A(1)R)-knockdown in SDH-INs, and the A(1)R-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.