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Here, we identified a circuit, locus coeruleus descending noradrenergic neurons projecting to the spinal dorsal horn (LC\n                    <jats:sup>\u2192SDH<\/jats:sup>\n                    -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\n                    <jats:sup>\u2192SDH<\/jats:sup>\n                    -NAergic terminals causing the stress-induced pain hypersensitivity was \u03b1\n                    <jats:sub>1A<\/jats:sub>\n                    -adrenaline receptors (\u03b1\n                    <jats:sub>1A<\/jats:sub>\n                    Rs) in\n                    <jats:italic>Hes5<\/jats:italic>\n                    -positive (\n                    <jats:italic>Hes5<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    ) astrocytes located in the SDH, an astrocyte subset that has an ability to induce pain sensitization. Furthermore, activation of\n                    <jats:italic>Hes5<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sub>1<\/jats:sub>\n                    -adenosine receptor (A\n                    <jats:sub>1<\/jats:sub>\n                    R)-knockdown in SDH-INs, and the A\n                    <jats:sub>1<\/jats:sub>\n                    R-knockdown suppressed pain hypersensitivity caused by acute restraint stress. Therefore, our findings suggest that LC\n                    <jats:sup>\u2192SDH<\/jats:sup>\n                    -NA neuronal signaling to\n                    <jats:italic>Hes5<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    SDH astrocytes and subsequent astrocytic reduction of SDH-IN activity are essential for mechanical pain facilitation caused by stress.\n                  <\/jats:p>","DOI":"10.7554\/elife.104453","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T06:25:19Z","timestamp":1741847119000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.104453","source":"Crossref","is-referenced-by-count":2,"title":["Descending locus coeruleus noradrenergic signaling to spinal astrocyte subset is required for stress-induced mechanical pain 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