{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T12:16:04Z","timestamp":1778847364623,"version":"3.51.4"},"reference-count":97,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["HL076125, HL141473, HL066299"],"award-info":[{"award-number":["HL076125, HL141473, HL066299"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["RICHTE16GO"],"award-info":[{"award-number":["RICHTE16GO"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of South Alabama Office of Research and Economic Development","award":["Research and Scholarly Development Grant"],"award-info":[{"award-number":["Research and Scholarly Development Grant"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Treatment with PAN-PDE4 inhibitors has been shown to produce hypothermia in multiple species. Given the growing body of evidence that links nausea and emesis to disturbances in thermoregulation in mammals, we explored PDE4 inhibitor-induced hypothermia as a novel correlate of nausea in mice. Using knockout mice for each of the four PDE4 subtypes, we show that selective inactivation of individual PDE4 subtypes per se does not produce hypothermia, which must instead require the concurrent inactivation of multiple (at least two) PDE4 subtypes. These findings contrast with the role of PDE4s in shortening the duration of \u03b12-adrenoceptor-dependent anesthesia, a behavioral surrogate previously used to assess the emetic potential of PDE4 inhibitors, which is exclusively affected by inactivation of PDE4D. These different outcomes are rooted in the distinct molecular mechanisms that drive these two paradigms; acting as a physiologic \u03b12-adrenoceptor antagonist produces the effect of PDE4\/PDE4D inactivation on the duration of \u03b12-adrenoceptor-dependent anesthesia, but does not mediate the effect of PDE4 inhibitors on body temperature in mice. Taken together, our findings suggest that selective inhibition of any individual PDE4 subtype, including inhibition of PDE4D, may be free of nausea and emesis.<\/jats:p>","DOI":"10.3390\/biology10121355","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T08:43:32Z","timestamp":1639989812000},"page":"1355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice"],"prefix":"10.3390","volume":"10","author":[{"given":"Abigail","family":"Boyd","sequence":"first","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5908-8153","authenticated-orcid":false,"given":"Ileana","family":"Aragon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Rich","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Will","family":"McDonough","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianna","family":"Oditt","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0062-7359","authenticated-orcid":false,"given":"Daniel","family":"Irelan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward","family":"Fiedler","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Abou Saleh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5588-9060","authenticated-orcid":false,"given":"Wito","family":"Richter","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1016\/S1359-6446(05)03622-6","article-title":"Keynote review: Phosphodiesterase-4 as a therapeutic target","volume":"10","author":"Houslay","year":"2005","journal-title":"Drug Discov. 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