{"doi":"10.1152/physiol.2025.40.s1.0272","title":"Melanocortin receptor 4 agonist, setmelanotide, treats opioid-induced respiratory depression","abstract":"The primary cause of death associated with opioids is opioid-induced respiratory depression (OIRD) and obesity is a major risk factor that increases mortality. Naloxone is used to reverse OIRD, but this drug is a competitive antagonist of µ-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. Previous studies suggest that melanocortin 4 receptor pathway (MC4R), which is implicated in body weight regulation, may impact control of breathing. An MC4R agonist, setmelanotide (SET), is approved by FDA to treat genetic obesity caused by abnormal melanocortin and leptin signaling. We hypothesized that SET can treat OIRD in mice. C57BL/6J male mice with diet-induced obesity were treated with IP morphine (10 mg/kg) and then 15 min later with either SET (1 mg/kg IP) or vehicle VEH (IP) in a random order. Breathing was recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. In mice with OIRD, SET induced a 3-fold reduction of the apnea index, from 67 ± 7 to 22 ± 4 events per hour (p < 0.001), and decreased apnea duration as compared to the VEH treatment. SET increased respiratory rate from 102 ± 4.5 to 130 ± 5.6 breaths per minute (p < 0.05). SET did not affect opioid analgesia. Photostimulation of MC4R+ ChR2-expressing fibers in the parafacial region elicited short-latency postsynaptic current in pre-motoneurons projecting to the phrenic motoneurons in the C3-C4 ventral horns of the spinal cord. In conclusion, SET effectively treated OIRD by increasing respiratory rate and inducing a significant decrease in the number of apneas without decreasing analgesia. Parafacial MC4R (+) neurons are a likely site of respiratory effects of SET. Support: NIH (R01 HL128970, R01 HL133100, and R01 HL138932), AHA (24CDA1270910). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.","journal":"Physiology","year":2025,"id":569467,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9491,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1385664,"name":"Noah Williams","orcid":"0000-0003-1467-7170","position":1,"is_corresponding":false},{"id":1474665,"name":"Melanie Alexis-Ruiz","orcid":null,"position":2,"is_corresponding":false},{"id":872277,"name":"O Aung","orcid":"0000-0002-5257-5696","position":3,"is_corresponding":false},{"id":471701,"name":"Olga Dergacheva","orcid":"0000-0003-1136-9156","position":4,"is_corresponding":false},{"id":1474666,"name":"Cole Winston","orcid":null,"position":5,"is_corresponding":false},{"id":413060,"name":"Joan B. Escobar","orcid":null,"position":6,"is_corresponding":false},{"id":1135577,"name":"Joshua East","orcid":null,"position":7,"is_corresponding":false},{"id":950688,"name":"Francis P. Sgambati","orcid":null,"position":8,"is_corresponding":false},{"id":317053,"name":"David Mendelowitz","orcid":"0000-0001-7107-1832","position":9,"is_corresponding":false},{"id":266238,"name":"Vsevolod Y. Polotsky","orcid":"0000-0002-2951-7535","position":10,"is_corresponding":false},{"id":576160,"name":"Mateus R. Amorim","orcid":"0000-0002-8490-4853","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:59.652443Z","pmid":"41959165","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}