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Presently, pharmacotherapy serves as a primary approach for NP alleviation, yet its efficacy often remains suboptimal. Melatonin (MLT), a biologically active compound secreted by the pineal gland, has long been associated with promoting and maintaining sleep. Although recent studies suggest analgesic effects of MLT, the underlying mechanism remains largely unknown, particularly its impact on the cortex. In this study, we induced an NP model in mice through spared nerve injury (SNI) and observed a considerable, dose-dependent alleviation in NP symptoms following intraperitoneal or anterior cingulate cortex (ACC) administration of MLT. Our findings further indicated that the NP management of MLT is selectively mediated by MLT-related receptor 2 (MT\n                    <jats:sub>2<\/jats:sub>\n                    R), rather than MT\n                    <jats:sub>1<\/jats:sub>\n                    R, on neurons and microglia within the ACC. Transcriptome sequencing, complemented by bioinformatics analysis, implicated MLT in the modulation of G\u03b1(i) and immune-inflammatory signals. Specifically, MLT inhibited the excitability level of pyramidal cells in the ACC by activating the G\u03b1(i) signaling pathway. Simultaneously, MLT attenuated M\n                    <jats:sub>1<\/jats:sub>\n                    polarization and promoted M\n                    <jats:sub>2<\/jats:sub>\n                    polarization of microglia, thereby mitigating the inflammatory response and type II interferon response within the ACC. These findings unveil a hitherto unrecognized molecular mechanism: an MLT-mediated neuroimmune modulation pathway in the ACC mediated by MT\n                    <jats:sub>2<\/jats:sub>\n                    R. This elucidation sheds light on the regulatory character of MLT in chronic nociceptive pain conditions, offering a prospective therapeutic strategy for NP management.\n                  <\/jats:p>","DOI":"10.34133\/research.0493","type":"journal-article","created":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T06:26:53Z","timestamp":1726208813000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":17,"title":["Melatonin Induces Analgesic Effects through MT\n                    <sub>2<\/sub>\n                    Receptor-Mediated Neuroimmune Modulation in the Mice Anterior Cingulate Cortex"],"prefix":"10.34133","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7478-1741","authenticated-orcid":false,"given":"Jian","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, \rFourth Military Medical University, Xi\u2019an 710032, China."},{"name":"Department of Neurosurgery, Tangdu Hospital, \rFourth Military Medical University, Xi\u2019an 710038, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1031-9327","authenticated-orcid":false,"given":"Junxiang","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, \rFourth Military Medical University, Xi\u2019an 710032, China."},{"name":"Department of Neurosurgery, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710004, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4966-2878","authenticated-orcid":false,"given":"Fujuan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, \rFourth Military Medical University, Xi\u2019an 710032, China."},{"name":"School of Medicine, Northwest University, Xi\u2019an 710069, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3218-7870","authenticated-orcid":false,"given":"Yi","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, \rFourth Military Medical University, Xi\u2019an 710032, China."},{"name":"School of Medicine, Northwest University, Xi\u2019an 710069, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. 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