{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T15:07:55Z","timestamp":1773414475876,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,10]]},"group-title":"Physiology","reference-count":62,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 HL174409, R01 HL128970, and R01 HL133100-S1"],"award-info":[{"award-number":["R01 HL174409, R01 HL128970, and R01 HL133100-S1"]}]},{"name":"AHA","award":["24CDA1270910"],"award-info":[{"award-number":["24CDA1270910"]}]},{"DOI":"10.13039\/501100001807","name":"FAPESP","doi-asserted-by":"crossref","award":["#2024\/13971-9"],"award-info":[{"award-number":["#2024\/13971-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The primary cause of death associated with opioids is opioid-induced respiratory depression (OIRD). Naloxone is used to reverse OIRD, but this drug is a competitive antagonist of \u00b5-opioid receptor (MOR) and reverses analgesia, which limits its therapeutic use. Alternative non-opioid receptor antagonist-based approaches to OIRD treatment and prevention are needed. The aim of this study was to evaluate if setmelanotide (SET) is capable of reversing OIRD in a mouse model.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>C57BL\/6J male and female mice and Sprague-Dawley rats were given IP morphine or fentanyl and then treated 15 min later with either SET or vehicle VEH (IP) in a random order. Breathing was recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In mice with OIRD, SET induced a 3-fold reduction of the apnea index, and decreased apnea duration as compared to the VEH treatment. SET increased respiratory rate and did not affect opioid-induced analgesia. Photostimulation of MC4R+ ChR2-expressing fibers in the parafacial region of MC4R-Cre mice elicited short-latency excitatory postsynaptic current in rostral ventral respiratory group (rVRG) pre-motoneurons projecting to the phrenic nucleus in the C3-C4 ventral horns of the spinal cord. Fentanyl inhibited the activity of rVRG neurons and SET reversed this effect.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>SET effectively treated OIRD by increasing respiratory rate and inducing a significant decrease in the number of apneas without decreasing analgesia.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.08.708886","type":"posted-content","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T04:45:18Z","timestamp":1773204318000},"source":"Crossref","is-referenced-by-count":0,"title":["Melanocortin receptor 4 agonist setmelanotide treats opioid-induced respiratory depression"],"prefix":"10.64898","author":[{"given":"Mateus R.","family":"Amorim","sequence":"first","affiliation":[{"name":"Department of Physiology, Medical School of Ribeir\u00e3o Preto, SP, Brazil"},{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noah R.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie A.","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junia L.","family":"de Deus","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"O","family":"Aung","sequence":"additional","affiliation":[{"name":"Medical College of Wisconsin, Milwaukee, WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga","family":"Dergacheva","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, George Washington University, Washington, DC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan","family":"Escobar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, George Washington University, Washington, DC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mi-Kyung","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cole R.","family":"Winston","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thales H. 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