{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T18:15:14Z","timestamp":1779387314148,"version":"3.53.1"},"reference-count":40,"publisher":"American Society for Clinical Investigation","issue":"10","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":45,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016698","name":"Joint Fund of the National Natural Science Foundation of China and the Karst Science Research Center of Guizhou Province","doi-asserted-by":"crossref","award":["82130034,82471254,82221001"],"award-info":[{"award-number":["82130034,82471254,82221001"]}],"id":[{"id":"10.13039\/100016698","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Brain Science and Brain-like Intelligence Technology - National Science and Technology Major Project","award":["2021ZD0204403"],"award-info":[{"award-number":["2021ZD0204403"]}]},{"name":"The Fourth Military Medical University Partner Lab Cooperation and Exchange Project","award":["2022HB002"],"award-info":[{"award-number":["2022HB002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,22]]},"abstract":"<jats:p>\n                    Chronic neuropathic pain is frequently comorbid with anxiety disorders, yet the neural circuits underlying this interaction remain poorly defined. The parafascicular nucleus (PF) of the thalamus integrates nociceptive and affective signals, but its specific regulatory mechanisms in pain-anxiety comorbidity are not well known. Using spared nerve injury (SNI) model mice, we combined viral neural tracing, chemogenetics, pharmacology, and electrophysiology to dissect the locus coeruleus (LC)\u2013PF neural pathway. Viral tracing revealed monosynaptic projections from norepinephrinergic (NEergic) neurons in the dorsal LC to Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \/calmodulin\u2013dependent protein kinase II\u03b1\u2013immunopositive (CaMKII\u03b1\n                    <jats:sup>+<\/jats:sup>\n                    ) neurons within the PF. Chemogenetic inhibition and activation of this pathway were performed in naive and SNI mice, alongside intra-PF microinjection of the \u03b1-2 adrenergic receptor (ADRA2) antagonist yohimbine. Behavioral tests assessed mechanical\/thermal hypersensitivity and anxiety-like behaviors. Results showed that 92.1% of PF-projecting LC neurons were NEergic, with 70.1% localized dorsally. Chemogenetic inhibition of the LC\n                    <jats:sup>NE<\/jats:sup>\n                    -PF\n                    <jats:sup>CaMKII\u03b1<\/jats:sup>\n                    neural pathway significantly alleviated both acute-phase mechanical hypersensitivity (&lt;7 days after surgery) and chronic-phase anxiety-like behaviors in SNI mice, while activation of this pathway induced pain sensitization and anxiety-like behaviors in naive mice. Intra-PF yohimbine reversed SNI-induced allodynia and anxiety-like behaviors. Electrophysiology confirmed that yohimbine increased PF neuronal intrinsic excitability. These results suggest that the LC\n                    <jats:sup>NE<\/jats:sup>\n                    -PF\n                    <jats:sup>CaMKII\u03b1<\/jats:sup>\n                    neural pathway promotes neuropathic pain and comorbid anxiety via ADRA2-mediated suppression of PF neuronal activity. Targeted inhibition of this circuit may represent a therapeutic strategy for pain-related affective disorders.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.198224","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T16:00:20Z","timestamp":1775577620000},"source":"Crossref","is-referenced-by-count":0,"title":["Norepinephrinergic projection from locus coeruleus to parafascicular nucleus promotes pain and anxiety-like behaviors in mice"],"prefix":"10.1172","volume":"11","author":[{"given":"Zhong-Yi","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."},{"name":"Department of Anatomy, Fujian Medical University, Fuzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Ming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."},{"name":"Department of Anatomy, School of Medicine, Dali University, Dali, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao-Hua","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."},{"name":"Department of Anatomy, Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."},{"name":"Department of Anatomy, Zunyi Medical University, Zunyi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Ang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."},{"name":"Department of Anatomy, School of Medicine, Zhengzhou University, Zhengzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."},{"name":"Department of Anatomy, Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Yu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."},{"name":"Department of Anatomy, Fujian Medical University, Fuzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Min","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."},{"name":"Department of Anatomy, Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Ning","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."},{"name":"Department of Anatomy, Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha-Sha","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."},{"name":"Department of Anatomy, Zunyi Medical University, Zunyi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9083-7776","authenticated-orcid":true,"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fen-Sheng","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience and Physiology, G\u00f6teborg University, G\u00f6teborg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Qing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi\u2019an, China."},{"name":"Department of Anatomy, School of Medicine, Dali University, Dali, China."},{"name":"Department of Anatomy, Zunyi Medical University, Zunyi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00393-7"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bja.2019.03.023"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2025.03.007"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00399.2013"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.01.009"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106332"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhab073"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-020-00692-4"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25168636"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.29808"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/cne.10236"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S0361-9230(96)00262-6"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2016.06.007"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202401855"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.11.024"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14282"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01455-9"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2024.01.014"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00811-x"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-022-00688-5"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-020-0360-9"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0283-1"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2826.2010.01988.x"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2021.11.023"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2013.01.067"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202501182"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.80100"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/cne.902170406"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(86)90156-9"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-13-1756-9_8"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01268-w"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20040822"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-011-2542-7"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-025-01921-6"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000002831"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4835-13.2014"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-024-04102-x"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-022-02525-8"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab239"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2025.107107"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/198224\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T18:01:28Z","timestamp":1779386488000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/198224"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,7]]},"references-count":40,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,3,26]]},"published-print":{"date-parts":[[2026,5,22]]}},"alternative-id":["10.1172\/jci.insight.198224"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.198224","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,7]]},"article-number":"e198224"}}