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Cholecystokinin-positive (CCK\n                    <jats:sup>+<\/jats:sup>\n                    ) neurons in the spinal dorsal horn (SDH) are critical for neuropathic pain, yet the underlying molecular mechanisms remain unclear. Here, we show that the membrane estrogen receptor G-protein coupled estrogen receptor (GPER\/GPR30) in spinal neurons was significantly upregulated in chronic constriction injury (CCI) mice and that inhibition of GPR30 in CCK\n                    <jats:sup>+<\/jats:sup>\n                    neurons reversed CCI-induced neuropathic pain. Furthermore, GPR30 in spinal CCK\n                    <jats:sup>+<\/jats:sup>\n                    neurons was essential for the enhancement of AMPA-mediated excitatory synaptic transmission in CCI mice. Moreover, GPR30 was expressed in spinal CCK\n                    <jats:sup>+<\/jats:sup>\n                    neurons that received direct projection from the primary sensory cortex (S1-SDH). Chemogenetic inhibition of S1-SDH post-synaptic neurons alleviated CCI-induced neuropathic pain. Conversely, chemogenetic activation of these neurons mimicked neuropathic pain symptoms, which were attenuated by spinal inhibition of GPR30. Finally, we confirmed that GPR30 in S1-SDH post-synaptic neurons was required for CCI-induced neuropathic pain. Taken together, our findings suggest that GPR30 in spinal CCK\n                    <jats:sup>+<\/jats:sup>\n                    neurons and S1-SDH post-synaptic neurons is pivotal for neuropathic pain, thereby representing a promising therapeutic target for neuropathic pain.\n                  <\/jats:p>","DOI":"10.7554\/elife.102874","type":"journal-article","created":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T13:25:17Z","timestamp":1733491517000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.102874","source":"Crossref","is-referenced-by-count":1,"title":["GPR30 in spinal cholecystokinin-positive neurons modulates neuropathic pain"],"prefix":"10.7554","volume":"13","author":[{"given":"Qing","family":"Chen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00a2xv884","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anesthesia, Women's Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"NANHU 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