{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:56:54Z","timestamp":1789171014541,"version":"build-2803163510"},"reference-count":56,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Opioid overdose suppresses brainstem respiratory circuits, causes apnoea and may result in death. Epidural electrical stimulation (EES) at the cervical spinal cord facilitated motor activity in rodents and humans, and we hypothesized that EES of the cervical spinal cord could antagonize opioid\u2010induced respiratory depression in humans. Eighteen patients requiring surgical access to the dorsal surface of the spinal cord between C2 and C7 received EES or sham stimulation for up to 90\u00a0s at 5 or 30\u00a0Hz during complete (OFF\u2010State) or partial suppression (ON\u2010State) of respiration induced by remifentanil. During the ON\u2010State, 30\u00a0Hz EES at C4 and 5\u00a0Hz EES at C3\/4 increased tidal volume and decreased the end\u2010tidal carbon dioxide level compared to pre\u2010stimulation control levels. EES of 5\u00a0Hz at C5 and C7 increased respiratory frequency compared to pre\u2010stimulation control levels. In the OFF\u2010State, 30\u00a0Hz cervical EES at C3\/4 terminated apnoea and induced rhythmic breathing. In cadaveric tissue obtained from a brain bank, more neurons expressed both the neurokinin 1 receptor (NK1R) and somatostatin (SST) in the cervical spinal levels responsive to EES (C3\/4, C6 and C7) compared to a region non\u2010responsive to EES (C2). Thus, the capacity of cervical EES to oppose opioid depression of respiration may be mediated by NK1R+\/SST+ neurons in the dorsal cervical spinal cord. This study provides proof of principle that cervical EES may provide a novel therapeutic approach to augment respiratory activity when the neural function of the central respiratory circuits is compromised by opioids or other pathological conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Epidural electrical stimulation (EES) using an implanted spinal cord stimulator (SCS) is an FDA\u2010approved method to manage chronic pain.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We tested the hypothesis that cervical EES facilitates respiration during administration of opioids in 18 human subjects who were treated with low\u2010dose remifentanil that suppressed respiration (ON\u2010State) or high\u2010dose remifentanil that completely inhibited breathing (OFF\u2010State) during the course of cervical surgery.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Dorsal cervical EES of the spinal cord augmented the respiratory tidal volume or increased the respiratory frequency, and the response to EES varied as a function of the stimulation frequency (5 or 30\u00a0Hz) and the cervical level stimulated (C2\u2013C7).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Short, continuous cervical EES restored a cyclic breathing pattern (eupnoea) in the OFF\u2010State, suggesting that cervical EES reversed the opioid\u2010induced respiratory depression.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These findings add to our understanding of respiratory pattern modulation and suggest a novel mechanism to oppose the respiratory depression caused by opioids.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp282664","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T14:54:31Z","timestamp":1654008871000},"page":"2973-2999","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Epidural electrical stimulation of the cervical spinal cord opposes opioid\u2010induced respiratory depression"],"prefix":"10.1113","volume":"600","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3575-3793","authenticated-orcid":false,"given":"Ruyi","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Neuromotor Recovery and Rehabilitation Center David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Interdepartmental Program in Neuroscience University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6631-4534","authenticated-orcid":false,"given":"Jason","family":"Worrell","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Neuromotor Recovery and Rehabilitation Center David Geffen School of Medicine University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6258-6698","authenticated-orcid":false,"given":"Eric","family":"Garner","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery David Geffen School of Medicine University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9244-2492","authenticated-orcid":false,"given":"Stephanie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Neuromotor Recovery and Rehabilitation Center David Geffen School of Medicine University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tali","family":"Homsey","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Neuromotor Recovery and Rehabilitation Center David Geffen School of Medicine University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4311-9864","authenticated-orcid":false,"given":"Bo","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Neuromotor Recovery and Rehabilitation Center David Geffen School of Medicine University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4687-0381","authenticated-orcid":false,"given":"Erika L.","family":"Galer","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Neuromotor Recovery and Rehabilitation Center David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Molecular, Cellular, Integrated Physiology Program University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7907-1148","authenticated-orcid":false,"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Neuromotor Recovery and Rehabilitation Center David Geffen School of Medicine University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3968-0464","authenticated-orcid":false,"given":"Sherwin","family":"Tavakol","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Keck School of Medicine University of Southern California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4269-6168","authenticated-orcid":false,"given":"Meelod","family":"Daneshvar","sequence":"additional","affiliation":[{"name":"University of California Fresno Department of Surgery  Fresno CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6159-674X","authenticated-orcid":false,"given":"Timothy","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Neuromotor Recovery and Rehabilitation Center David Geffen School of Medicine University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2965-1240","authenticated-orcid":false,"given":"Harry V.","family":"Vinters","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Brain Research Institute University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3520-9467","authenticated-orcid":false,"given":"Noriko","family":"Salamon","sequence":"additional","affiliation":[{"name":"Department of Radiology David Geffen School of Medicine University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3385-1314","authenticated-orcid":false,"given":"David L.","family":"McArthur","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery David Geffen School of Medicine University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6916-153X","authenticated-orcid":false,"given":"Marc R.","family":"Nuwer","sequence":"additional","affiliation":[{"name":"Department of Neurology David Geffen School of Medicine University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4780-8600","authenticated-orcid":false,"given":"Irene","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology David Geffen School of Medicine University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8572-6035","authenticated-orcid":false,"given":"James C.","family":"Leiter","sequence":"additional","affiliation":[{"name":"Department of Molecular and Systems Biology Geisel School of Medicine  Lebanon NH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2162-3672","authenticated-orcid":false,"given":"Daniel C.","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Neuromotor Recovery and Rehabilitation Center David Geffen School of Medicine University of California  Los Angeles CA USA"},{"name":"Interdepartmental Program in Neuroscience University of California  Los Angeles CA USA"},{"name":"Brain Research Institute University of California  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,31]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(80)80034-5"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15580"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00895.2017"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/EJA.0000000000000223"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2019.00143"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajem.2019.09.014"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/emj.2003.009613"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.09.076"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/PHM.0000000000001018"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/10790268.2019.1699678"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2010.199679"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apmr.2008.11.014"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apmr.2004.11.027"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-152-2-201001190-00006"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/2192568217701914"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010018\u201033123\u20105"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00913.2016"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn0901-927"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnhum.2017.00144"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2017.04.011"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1958.02990130006002"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2016.08.018"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00473.2016"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1310\/sci1804-315"},{"key":"e_1_2_5_26_1","first-page":"371","article-title":"10\u201320 System","author":"Jasper H. H.","year":"1958","journal-title":"Int Fed"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnsys.2019.00084"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-88-470-2916-3_26"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0123022"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12576-010-0091-1"},{"key":"e_1_2_5_31_1","first-page":"4431","article-title":"Impact of chronic intermittent spinal cord stimulation (SCS) on airway pressure generation (P) for cough production in spinal cord injury (SCI)","volume":"44","author":"Kowalski K.","year":"2014","journal-title":"European Respiratory Journal"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2013.03.006"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2016.07.001"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01054.2018"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0426-21.2021"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0116\u201319.2019"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1017\/cem.2019.471"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(95)00088-7"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1179\/016164110X12807570510130"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1080\/15360288.2019.1668902"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1995.sp020584"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2017.5082"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8986.1993.tb02081.x"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.5188"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.12703\/P6\u201079"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e31821f0522"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.31616\/asj.2020.0227"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0031-15.2015"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-03180-w"},{"key":"e_1_2_5_50_1","first-page":"544","article-title":"Naloxone\u2010precipitated acute opioid withdrawal syndrome after epidural morphine","volume":"86","author":"Sun H. L.","year":"1998","journal-title":"Anesthesia and Analgesia"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003\u2010020\u201001604\u2010x"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2019.103339"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2104"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.22753"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP278612"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1360-0443.1999.9479612.x"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1111\/ner.12903"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP282664","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP282664","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP282664","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T22:05:38Z","timestamp":1692828338000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP282664"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,31]]},"references-count":56,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["10.1113\/JP282664"],"URL":"https:\/\/doi.org\/10.1113\/jp282664","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,31]]},"assertion":[{"value":"2021-12-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}