{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T03:49:38Z","timestamp":1781236178939,"version":"3.54.1"},"reference-count":57,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2020,6,14]],"date-time":"2020-06-14T00:00:00Z","timestamp":1592092800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["POST35030003"],"award-info":[{"award-number":["POST35030003"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["GRNT 25710176"],"award-info":[{"award-number":["GRNT 25710176"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["T32 HL074466"],"award-info":[{"award-number":["T32 HL074466"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["P01 HL088052"],"award-info":[{"award-number":["P01 HL088052"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Sleep apnoea increases susceptibility to opioid\u2010induced respiratory depression (OIRD).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Endogenous opioids are implicated as a contributing factor in sleep apnoea.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Rats exposed to sleep\u2010phase chronic intermittent hypercapnic hypoxia (CIHH) for 7\u00a0days exhibited exaggerated OIRD to systemic fentanyl both while anaesthetized and artificially ventilated and while conscious and breathing spontaneously, implicating heightened CNS inhibitory efficacy of fentanyl.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>CIHH also induced tonic endogenous opioid suppression of neural inspiration.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Sleep\u2010related episodes of hypercapnic hypoxia, as in sleep apnoea, promote hypersensitivity to OIRD, with tonic respiratory depression by endogenous opioids implicated as a potential underlying cause.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Sleep apnoea (SA) increases opioid\u2010induced respiratory depression (OIRD) and lethality. To test the hypothesis that this results from chronic intermittent bouts of hypercapnic hypoxia (CIHH) accompanying SA, we compared OIRD across continuously normoxic control rats and rats exposed to sleep\u2010phase (8\u00a0h\/day) CIHH for 1\u00a0week. OIRD sensitivity was first assessed in anaesthetized (urethane\/\u03b1\u2010chloralose), vagotomized and artificially ventilated rats by recording phrenic nerve activity (PNA) to index neural inspiration and quantify PNA burst inhibition to graded doses (0, 2, 20, 50\u00a0\u03bcg\u00a0kg<jats:sup>\u20101<\/jats:sup>, <jats:sc>i.v.<\/jats:sc>) of the synthetic opioid fentanyl. Fentanyl dose\u2010dependently reduced PNA burst frequency (<jats:italic>P\u00a0=\u00a0<\/jats:italic>0.0098\u20130.0001), while increasing the duration of burst quiescence at 50\u00a0\u03bcg\u00a0kg<jats:sup>\u20101<\/jats:sup> (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001, <jats:italic>n<\/jats:italic>\u00a0=\u00a05\u20136\/group\/dose). CIHH shifted the fentanyl dose\u2013phrenic burst frequency response curve to the left (<jats:italic>P\u00a0=\u00a0<\/jats:italic>0.0163) and increased the duration of burst quiescence (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001). During fentanyl recovery, PNA burst width was increased relative to baseline in normoxic and CIHH rats. Systemic naloxone (1\u00a0mg\u00a0kg<jats:sup>\u20101<\/jats:sup>, <jats:sc>i.v.<\/jats:sc>) reversed fentanyl\u2010induced PNA arrest in both groups (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0002), and increased phrenic burst amplitude above baseline (<jats:italic>P\u00a0=\u00a0<\/jats:italic>0.0113) in CIHH rats only. Differential sensitivity to anaesthesia as a cause of CIHH\u2010related OIRD hypersensitivity was excluded by observing in conscious spontaneously breathing rats that fentanyl at 20\u00a0\u03bcg\u00a0kg<jats:sup>\u20101<\/jats:sup> (<jats:sc>i.v.<\/jats:sc>), which silenced PNA in anaesthetized rats, differentially increased breathing variability in normoxic <jats:italic>versus<\/jats:italic> CIHH rats (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0427), while significantly reducing breathing frequency (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) and periodicity (<jats:italic>P\u00a0=\u00a0<\/jats:italic>0.0003) in CIHH rats only. Findings indicate that CIHH increased OIRD sensitivity, with tonic inspiratory depression by endogenous opioids as a likely contributing cause.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp280021","type":"journal-article","created":{"date-parts":[[2020,5,16]],"date-time":"2020-05-16T14:19:26Z","timestamp":1589638766000},"page":"3239-3257","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Intermittent hypercapnic hypoxia induces respiratory hypersensitivity to fentanyl accompanied by tonic respiratory depression by endogenous opioids"],"prefix":"10.1113","volume":"598","author":[{"given":"Allison D.","family":"Brackley","sequence":"first","affiliation":[{"name":"Department of Cellular and Integrative Physiology University of Texas Health San Antonio  7703 Floyd Curl Drive San Antonio TX 78229"},{"name":"Center for Biomedical Neuroscience University of Texas Health San Antonio  7703 Floyd Curl Drive San Antonio TX 78229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Ann","family":"Andrade","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology University of Texas Health San Antonio  7703 Floyd Curl Drive San Antonio TX 78229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3100-746X","authenticated-orcid":false,"given":"Glenn M.","family":"Toney","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology University of Texas Health San Antonio  7703 Floyd Curl Drive San Antonio TX 78229"},{"name":"Center for Biomedical Neuroscience University of Texas Health San Antonio  7703 Floyd Curl Drive San Antonio TX 78229"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,14]]},"reference":[{"key":"e_1_2_5_2_1","first-page":"233","article-title":"Naloxone improves sleep apnea in obese humans","volume":"9","author":"Atkinson RL","year":"1985","journal-title":"Int J Obes"},{"key":"e_1_2_5_3_1","volume-title":"The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications: Version 2.3","author":"Berry RB","year":"2016"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/0310057X0803600309"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11325-006-0064-z"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2016.12.005"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200105000-00021"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.03603"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2017.11.015"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2016.09.038"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1042\/cs0670465"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03006641"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000000997"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1288\/00005537-198911000-00004"},{"key":"e_1_2_5_15_1","first-page":"S51","article-title":"New Perspectives in the Treatment of Opioid\u2010Induced Respiratory Depression","volume":"8","author":"Fala L","year":"2015","journal-title":"American Health Drug Benefits"},{"key":"e_1_2_5_16_1","first-page":"695","article-title":"[Efficacy of the treatment of sleep apnea using naltrexone. 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