{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T14:50:16Z","timestamp":1783003816678,"version":"3.54.5"},"reference-count":68,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2019,1,1]],"date-time":"2019-01-01T00:00:00Z","timestamp":1546300800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81471129"],"award-info":[{"award-number":["81471129"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81671087"],"award-info":[{"award-number":["81671087"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771142"],"award-info":[{"award-number":["81771142"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Mol Pain"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:p>Preoperative anxiety is common in patients undergoing elective surgery and is closely related to postoperative hyperalgesia. In this study, a single prolonged stress model was used to induce preoperative anxiety-like behavior in rats 24 h before the surgery. We found that single prolonged stress exacerbated the postoperative pain and elevated the level of serum corticosterone. Previous studies have shown that glucocorticoid is associated with synaptic plasticity, and decreased spinal GABAergic activity can cause hyperalgesia in rodents. Here, single prolonged stress rats\u2019 lumbar spinal cord showed reduced glutamic acid decarboxylase-65, glutamic acid decarboxylase-67, GABA type A receptor alpha 1 subunit, and GABA type A receptor gamma 2 subunit, indicating an impairment of GABAergic system. Furthermore, neuronal PAS domain protein 4 was also reduced in rats after single prolonged stress stimulation, which has been reported to promote GABAergic synapse development. Then, intraperitoneal injection of RU486 (a glucocorticoid receptor antagonist) rather than spironolactone (a mineralocorticoid receptor antagonist) was found to relieve single prolonged stress-induced hyperalgesia and reverse neuronal PAS domain protein 4 reduction and the impairment of GABAergic system. Furthermore, overexpressing neuronal PAS domain protein 4 could also restore the damage of GABAergic system caused by single prolonged stress while interfering with neuronal PAS domain protein 4 caused an opposite effect. Finally, after stimulation of rat primary spinal cord neurons with exogenous corticosterone in vitro, neuronal PAS domain protein 4 and GABAergic markers were also downregulated, and RU486 reversed that. Together, our results demonstrated that preoperative anxiety led to GABAergic system impairment in spinal cord and thus caused hyperalgesia due to glucocorticoid-induced downregulation of neuronal PAS domain protein 4.<\/jats:p>","DOI":"10.1177\/1744806919850383","type":"journal-article","created":{"date-parts":[[2019,5,1]],"date-time":"2019-05-01T07:46:46Z","timestamp":1556696806000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":23,"title":["Preoperative anxiety-induced glucocorticoid signaling reduces GABAergic markers in spinal cord and promotes postoperative hyperalgesia by affecting neuronal PAS domain protein 4"],"prefix":"10.1177","volume":"15","author":[{"given":"Hao","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuoxia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanting","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenchen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengliang","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,5,27]]},"reference":[{"key":"bibr1-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000000286"},{"key":"bibr2-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4637.2009.00730.x"},{"key":"bibr3-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1097\/01.ajp.0000135236.12705.2d"},{"key":"bibr4-1744806919850383","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.jpain.2015.08.001","volume":"16","author":"Richez B","year":"2015","journal-title":"J Pain"},{"key":"bibr5-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1002\/da.20600"},{"key":"bibr6-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2009.04.003"},{"key":"bibr7-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2009.05.059"},{"key":"bibr8-1744806919850383","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1097\/FBP.0b013e3282f007cb","volume":"18","author":"Fereidoni M","year":"2007","journal-title":"Behav Pharmacol"},{"key":"bibr9-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.11.003"},{"key":"bibr10-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2009.04.001"},{"key":"bibr11-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2015.06.006"},{"key":"bibr12-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3058-04.2004"},{"key":"bibr13-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.02.007"},{"key":"bibr14-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-15-06724.2002"},{"key":"bibr15-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2011.04.017"},{"key":"bibr16-1744806919850383","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.neuropharm.2011.01.034","volume":"60","author":"Cao J","year":"2011","journal-title":"Neuropharmacology"},{"key":"bibr17-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2013.07.024"},{"key":"bibr18-1744806919850383","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1111\/j.1460-9568.2004.03568.x","volume":"20","author":"Verkuyl JM","year":"2004","journal-title":"Eur J Neurosci"},{"key":"bibr19-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2004.03846.x"},{"key":"bibr20-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2007.12.022"},{"key":"bibr21-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1038\/nature07319"},{"key":"bibr22-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1038\/nature12743"},{"key":"bibr23-1744806919850383","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1016\/j.cell.2014.03.058","volume":"157","author":"Spiegel I","year":"2014","journal-title":"Cell"},{"key":"bibr24-1744806919850383","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.celrep.2014.06.056","volume":"8","author":"Yoshihara S","year":"2014","journal-title":"Cell Rep"},{"key":"bibr25-1744806919850383","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1111\/j.1471-4159.2010.06893.x","volume":"114","author":"Yun J","year":"2010","journal-title":"J Neurochem"},{"key":"bibr26-1744806919850383","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.bbr.2015.04.027","volume":"295","author":"Coutellier L","year":"2015","journal-title":"Behav Brain Res"},{"key":"bibr27-1744806919850383","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.3892\/etm.2014.1537","volume":"7","author":"Zhang Z","year":"2014","journal-title":"Exp Ther Med"},{"key":"bibr28-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4530(97)00044-9"},{"key":"bibr29-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(95)01441-1"},{"key":"bibr30-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1401811111"},{"key":"bibr31-1744806919850383","doi-asserted-by":"crossref","first-page":"3235","DOI":"10.1007\/s12035-015-9223-1","volume":"53","author":"Guo Y","year":"2016","journal-title":"Mol Neurobiol"},{"key":"bibr32-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2011.09.028"},{"key":"bibr33-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.12.6496"},{"key":"bibr34-1744806919850383","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cell.2009.08.027","volume":"139","author":"Betley JN","year":"2009","journal-title":"Cell"},{"key":"bibr35-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(98)01270-X"},{"key":"bibr36-1744806919850383","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.conb.2010.06.001","volume":"20","author":"Smith KR","year":"2010","journal-title":"Curr Opin Neurobiol"},{"key":"bibr37-1744806919850383","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1046\/j.1471-4159.2001.00664.x","volume":"79","author":"Ali NJ","year":"2001","journal-title":"J Neurochem"},{"key":"bibr38-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1038\/2798"},{"key":"bibr39-1744806919850383","doi-asserted-by":"crossref","first-page":"7698","DOI":"10.1073\/pnas.91.16.7698","volume":"91","author":"Otis TS","year":"1994","journal-title":"Proc Natl Acad Sci U S A"},{"key":"bibr40-1744806919850383","doi-asserted-by":"crossref","first-page":"8851","DOI":"10.1523\/JNEUROSCI.0979-11.2011","volume":"31","author":"Lin HC","year":"2011","journal-title":"J Neurosci"},{"key":"bibr41-1744806919850383","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1523\/JNEUROSCI.1622-11.2011","volume":"32","author":"Smith KR","year":"2012","journal-title":"J Neurosci"},{"key":"bibr42-1744806919850383","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00136"},{"key":"bibr43-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2003.017962"},{"key":"bibr44-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2003.018911"},{"key":"bibr45-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2003.036400"},{"key":"bibr46-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2013.04.016"},{"key":"bibr47-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000000161"},{"key":"bibr48-1744806919850383","first-page":"73","volume":"11","author":"Cao J","year":"2015","journal-title":"Mol Pain"},{"key":"bibr49-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13102"},{"key":"bibr50-1744806919850383","doi-asserted-by":"crossref","first-page":"e91393","DOI":"10.1371\/journal.pone.0091393","volume":"9","author":"Le Coz GM","year":"2014","journal-title":"PLoS One"},{"key":"bibr51-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2012.253"},{"key":"bibr52-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3387"},{"key":"bibr53-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20644"},{"key":"bibr54-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.490270315"},{"key":"bibr55-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-016-9976-1"},{"key":"bibr56-1744806919850383","doi-asserted-by":"crossref","unstructured":"Zhang Z, Wu H, Liu YGu X, Zhang W and Ma Z. The GCs-SGK1-ATP signaling pathway in spinal astrocytes underlied presurgical anxiety-induced postsurgical hyperalgesia.\n                      Anesth Analg\n                      2018.","DOI":"10.1213\/ANE.0000000000003682"},{"key":"bibr57-1744806919850383","doi-asserted-by":"crossref","first-page":"e85768","DOI":"10.1371\/journal.pone.0085768","volume":"9","author":"Bersten DC","year":"2014","journal-title":"PLoS One"},{"key":"bibr58-1744806919850383","doi-asserted-by":"crossref","first-page":"2808","DOI":"10.2337\/db12-1527","volume":"62","author":"Sabatini PV","year":"2013","journal-title":"Diabetes"},{"key":"bibr59-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-013-1505-7"},{"key":"bibr60-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2007.05207.x"},{"key":"bibr61-1744806919850383","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.brainres.2017.11.024","volume":"1679","author":"Drouet JB","year":"2018","journal-title":"Brain Res"},{"key":"bibr62-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2013.11.008"},{"key":"bibr63-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-15-06810.2002"},{"key":"bibr64-1744806919850383","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1080\/14734220600621344","volume":"5","author":"Drake-Baumann R.","year":"2006","journal-title":"Cerebellum"},{"key":"bibr65-1744806919850383","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1111\/jnc.12034","volume":"123","author":"Furukawa-Hibi Y","year":"2012","journal-title":"J Neurochem"},{"key":"bibr66-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2005.10.015"},{"key":"bibr67-1744806919850383","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4127-04.2005"},{"key":"bibr68-1744806919850383","doi-asserted-by":"crossref","first-page":"13737","DOI":"10.1523\/JNEUROSCI.2130-14.2014","volume":"34","author":"Li C","year":"2014","journal-title":"J Neurosci"}],"container-title":["Molecular Pain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/1744806919850383","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/1744806919850383","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/1744806919850383","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T08:17:16Z","timestamp":1777709836000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/1744806919850383"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1]]},"references-count":68,"alternative-id":["10.1177\/1744806919850383"],"URL":"https:\/\/doi.org\/10.1177\/1744806919850383","relation":{},"ISSN":["1744-8069","1744-8069"],"issn-type":[{"value":"1744-8069","type":"print"},{"value":"1744-8069","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1]]},"article-number":"1744806919850383"}}