PT  - JOURNAL ARTICLE
AU  - Kawanabe-Kobayashi, Riku
AU  - Uchiyama, Sawako
AU  - Yoshihara, Kohei
AU  - Kojima, Daiki
AU  - McHugh, Thomas
AU  - Hatada, Izuho
AU  - Matsui, Ko
AU  - Tanaka, Kenji F.
AU  - Tsuda, Makoto
TI  - Descending locus coeruleus noradrenergic signaling to spinal astrocyte subset is required for stress-induced pain facilitation
AID  - 10.1101/2024.11.14.623627
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.11.14.623627
4099  - http://biorxiv.org/content/early/2024/11/14/2024.11.14.623627.short
4100  - http://biorxiv.org/content/early/2024/11/14/2024.11.14.623627.full
AB  - 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 α1A-adrenaline receptors (α1ARs) 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 pain facilitation caused by stress.Competing Interest StatementThe authors have declared no competing interest.