{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T14:26:59Z","timestamp":1784816819637,"version":"3.55.0"},"reference-count":84,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["PO1HL101871"],"award-info":[{"award-number":["PO1HL101871"]}]},{"name":"NIDA","award":["U01DA051373"],"award-info":[{"award-number":["U01DA051373"]}]},{"name":"Galleon Pharmaceuticals, Inc.","award":["GAL-10,001, 10,002, 10,003"],"award-info":[{"award-number":["GAL-10,001, 10,002, 10,003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: We examined the role of muscarinic cholinergic receptors in the ventilatory depressant effects of morphine in male Sprague Dawley rats, and in responses elicited by a hypoxic-hypercapnic gas (HH) challenge and upon return to room air. Methods: Ventilatory parameters were measured in freely moving rats by whole body plethysmography that continuously recorded these parameters. Results: The injection of morphine (10 mg\/kg, IV) elicited a relatively pronounced depression of breathing, including sustained decreases in tidal volume, minute ventilation, peak inspiratory flow, and inspiratory and expiratory drives that were associated with marked increases in end inspiratory pause (EIP), expiratory flow at 50% expired tidal volume (EF50), and the rate of achieving peak expiratory flow (Rpef). Subsequent injection of the muscarinic receptor antagonist, atropine (1 mg\/kg, IV), in morphine-treated rats did not affect the frequency of breathing, tidal volume, minute ventilation, inspiratory and expiratory times, end expiratory pause, peak inspiratory and expiratory flows, relaxation time, expiratory delay, apneic pause, inspiratory and expiratory drives, and the non-eupneic breathing index (p &gt; 0.05 for all comparisons). In contrast, atropine dramatically reduced the morphine-induced increases in EIP, Rpef and EF50 (p &lt; 0.05, for all comparisons). In addition, the changes in many ventilatory parameters (e.g., frequency of breathing, tidal volume and minute ventilation) that occurred during a subsequent HH-challenge and upon the return to room air were markedly reduced in atropine-treated rats (p &lt; 0.05, for all comparisons). Conclusions: These findings suggest that muscarinic receptors play a limited, but important role, in the expression of the ventilatory effects of morphine in male rats and a substantial role in the expression of responses elicited during and following HH-challenge.<\/jats:p>","DOI":"10.3390\/ph19071101","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:47:32Z","timestamp":1784508452000},"page":"1101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Role of Muscarinic Receptor Signaling Processes in Specific Aspects of Morphine-Induced Respiratory Depression in Rats"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8278-0810","authenticated-orcid":false,"given":"Paulina M.","family":"Getsy","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Pulmonology, Allergy and Immunology, School of Medicine, Biomedical Research Building, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter J.","family":"May","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santhosh M.","family":"Baby","sequence":"additional","affiliation":[{"name":"Galleon Pharmaceuticals, Inc., 213 Witmer Road, Horsham, PA 19044, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory A.","family":"Coffee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pulmonology, Allergy and Immunology, School of Medicine, Biomedical Research Building, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunguang","family":"Qiu","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA"},{"name":"Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1736-2847","authenticated-orcid":false,"given":"Feixiong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA"},{"name":"Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6898-9527","authenticated-orcid":false,"given":"James N.","family":"Bates","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Iowa Hospitals and Clinics, Iowa, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pulmonology, Allergy and Immunology, School of Medicine, Biomedical Research Building, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1097\/ALN.0b013e3181c38c25","article-title":"Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression","volume":"112","author":"Dahan","year":"2010","journal-title":"Anesthesiology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5994","DOI":"10.2174\/138161212803582469","article-title":"Non-analgesic effects of opioids: Opioid-induced respiratory depression","volume":"18","author":"Boom","year":"2012","journal-title":"Curr. 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