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bioRxiv · 10.1101/2024.11.14.623627

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

Kawanabe-Kobayashi, R.·Uchiyama, S.·Yoshihara, K.·Kojima, D.·McHugh, T. J.·Hatada, I.·Matsui, K.·Tanaka, K. F.·Tsuda, M.
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Abstract

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 1A-adrenaline receptors (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.

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Kawanabe-Kobayashi, R., Uchiyama, S., Yoshihara, K., Kojima, D., McHugh, T. J., Hatada, I., Matsui, K., Tanaka, K. F., Tsuda, M.. 2024-11-14. Descending locus coeruleus noradrenergic signaling to spinal astrocyte subset is required for stress-induced pain facilitation. https://doi.org/10.1101/2024.11.14.623627

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