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Kainate receptors (KARs) are ionotropic glutamate receptors that regulate the release of both excitatory and inhibitory neurotransmitters in several brain areas, such as the anterior cingulate cortex (ACC), which is an important part of the brain for processing pain and emotions. KAR-dependent long-term potentiation (LTP) in the ACC has been proven to contribute to chronic pain. However, the existence of KAR-mediated LTD and its functional relevance to chronic pain remain unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A multidisciplinary approach combining multi-channel field potential recording, whole-cell patch-clamp recording, and pharmacological assays was used to characterize KAR-mediated LTD in the ACC. The regulatory role of KAR-mediated LTD in chronic pain was evaluated using the spared nerve injury (SNI) mouse model, along with viral overexpression and knockdown techniques, as well as pharmacological administration of the KAR agonist ATPA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Application of the KAR agonist kainic acid (KA) or the GluK1-selective agonist ATPA induced robust, dose-dependent LTD. The induction of LTD required the GluK1 subunit and L-type voltage-gated calcium channels but was independent of NMDA receptors. The Ca\u00b2\u207a-activated PKA signaling pathway regulated this LTD, and presynaptic inhibition via GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptors was also involved. In spared nerve injury (SNI) mice, KAR-mediated LTD was occluded in the ACC. Knockdown of GluK1-containing KARs in excitatory neurons or their overexpression in inhibitory neurons produced analgesic effects in SNI mice. Moreover, intra-ACC microinjection of the GluK1 agonist ATPA attenuated mechanical and thermal hyperalgesia in both neuropathic and inflammatory pain models, without affecting anxiety-like responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identified a novel form of KAR\u2011mediated LTD in the ACC that depends on GluK1\u2011containing KARs and the Ca\u00b2\u207a\u2011activated PKA signaling pathway. This form of LTD is involved in modulating chronic pain. These findings suggest that GluK1-containing KARs in the ACC represent a potential intervention node for chronic pain, warranting further preclinical investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08667-0","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T14:12:57Z","timestamp":1784297577000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["GluK1-containing kainate receptor-dependent long-term depression in the anterior cingulate cortex modulates chronic pain"],"prefix":"10.1186","volume":"24","author":[{"given":"Zhi-Xia","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Yuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxiong","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingmin","family":"Che","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4376-6252","authenticated-orcid":false,"given":"Xu-Hui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"issue":"8","key":"8667_CR1","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/nrn.2016.68","volume":"17","author":"TV Bliss","year":"2016","unstructured":"Bliss TV, Collingridge GL, Kaang BK, Zhuo M. 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