{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:15:41Z","timestamp":1785428141699,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,24]]},"group-title":"Pharmacology and Toxicology","reference-count":24,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["UG3DA062506"],"award-info":[{"award-number":["UG3DA062506"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Opioid addiction and misuse are a serious national crisis that affects public health, as well as social and economic welfare. Mortality due to opioid misuse is further exasperated by the combination of opioids with non-opioid respiratory depressants such as xylazine that are resistant to mu opioid receptor antagonists such as naloxone. This study tested the hypothesis that oxytocin can mitigate the severe opioid induced respiratory depression (OIRD) and mortality induced by high doses of fentanyl or the combination of fentanyl with xylazine. Our results show OXT can improve survival and respiratory function in both male and female rats with opioid induced respiratory depression caused by fentanyl, as well as a combination of fentanyl and xylazine. The improvement in respiratory function by OXT post fentanyl-xylazine was significantly greater than the recovery using only naloxone. Chemogenetic activation of OXT receptor positive neurons in the ventral respiratory group (VRG) provided similar benefits to that of OXT administration in reversing OIRD. These results indicate OXT is a promising therapeutic target for reversing OIRD and the respiratory depression that occurs with the combination of opioids and xylazine, a situation where naloxone is only partially effective. Additional translational benefits of OXT include it can be repurposed as it is already a FDA approved drug for other uses, has a high safety profile, and is unlikely to induce the withdrawal or reversal of analgesia that occurs with naloxone.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Oxytocin (OXT) improves survival and respiratory function in both male and female rats with opioid induced respiratory depression (OIRD) caused by fentanyl<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>OXT also reverses OIRD induced by the combination of fentanyl and xylazine<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>The improvement in respiratory function by OXT post fentanyl-xylazine was significantly greater than the recovery using only naloxone<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Chemogenetic activation of OXT receptor positive neurons in the ventral respiratory group (VRG) provided similar benefits to that of OXT administration in reversing OIRD<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>These results indicate OXT is a promising therapeutic target for reversing OIRD and the respiratory depression that occurs with the combination of opioids and xylazine<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.23.702914","type":"posted-content","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T23:45:14Z","timestamp":1771976714000},"source":"Crossref","is-referenced-by-count":1,"title":["Oxytocin treats respiratory depression and reduces mortality from fentanyl and the combination of xylazine-fentanyl"],"prefix":"10.64898","author":[{"given":"Joan B.","family":"Escobar","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Wainwright","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Dergacheva","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W.","family":"Kay","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, The George Washington University, Washington, DC 20052"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Bethea","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, George Washington University, Washington, DC 20037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Pulmonary, Critical Care, and Sleep Disorders Medicine, George Washington University, Washington, DC 20037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vsevolod Y.","family":"Polotsky","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC 20037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7107-1832","authenticated-orcid":false,"given":"David","family":"Mendelowitz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026022708300861000_2026.02.23.702914v1.1","doi-asserted-by":"crossref","first-page":"5827","DOI":"10.1113\/JP287845","article-title":"Oxytocinergic signalling in the respiratory parafacial region increases the activity of chemosensitive neurons and respiratory output","volume":"603","year":"2025","journal-title":"J 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