{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:21:38Z","timestamp":1791638498927,"version":"4.3.4"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,16]],"date-time":"2020-12-16T00:00:00Z","timestamp":1608076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["ZIA DK075062"],"award-info":[{"award-number":["ZIA DK075062"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["ZIA DK075063"],"award-info":[{"award-number":["ZIA DK075063"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["ZIA DK070002"],"award-info":[{"award-number":["ZIA DK070002"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Extracellular adenosine, a danger signal, can cause hypothermia. We generated mice lacking neuronal adenosine A<jats:sub>1<\/jats:sub> receptors (A<jats:sub>1<\/jats:sub>AR, encoded by the <jats:italic>Adora1<\/jats:italic> gene) to examine the contribution of these receptors to hypothermia. Intracerebroventricular injection of the selective A<jats:sub>1<\/jats:sub>AR agonist (Cl-ENBA, 5'-chloro-5'-deoxy-<jats:italic>N<\/jats:italic><jats:sup><jats:italic>6<\/jats:italic><\/jats:sup>-endo-norbornyladenosine) produced hypothermia, which was reduced in mice with deletion of A<jats:sub>1<\/jats:sub>AR in neurons. A non-brain penetrant A<jats:sub>1<\/jats:sub>AR agonist [SPA, <jats:italic>N<\/jats:italic><jats:sup><jats:italic>6<\/jats:italic><\/jats:sup>-(p-sulfophenyl) adenosine] also caused hypothermia, in wild type but not mice lacking neuronal A<jats:sub>1<\/jats:sub>AR, suggesting that peripheral neuronal A<jats:sub>1<\/jats:sub>AR can also cause hypothermia. Mice expressing Cre recombinase from the <jats:italic>Adora1<\/jats:italic> locus were generated to investigate the role of specific cell populations in body temperature regulation. Chemogenetic activation of Adora1-Cre-expressing cells in the preoptic area did not change body temperature. In contrast, activation of Adora1-Cre-expressing dorsomedial hypothalamus cells increased core body temperature, concordant with agonism at the endogenous inhibitory A<jats:sub>1<\/jats:sub>AR causing hypothermia. These results suggest that A<jats:sub>1<\/jats:sub>AR agonism causes hypothermia via two distinct mechanisms: brain neuronal A<jats:sub>1<\/jats:sub>AR and A<jats:sub>1<\/jats:sub>AR on neurons outside the blood-brain barrier. The variety of mechanisms that adenosine can use to induce hypothermia underscores the importance of hypothermia in the mouse response to major metabolic stress or injury.<\/jats:p>","DOI":"10.1371\/journal.pone.0243986","type":"journal-article","created":{"date-parts":[[2020,12,16]],"date-time":"2020-12-16T20:57:02Z","timestamp":1608152222000},"page":"e0243986","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Activation of neuronal adenosine A1 receptors causes hypothermia through central and peripheral mechanisms"],"prefix":"10.1371","volume":"15","author":[{"given":"Haley S.","family":"Province","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuiying","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison S.","family":"Mogul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankita","family":"Sahoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8104-1493","authenticated-orcid":true,"given":"Kenneth A.","family":"Jacobson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram\u00f3n A.","family":"Pi\u00f1ol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oksana","family":"Gavrilova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0426-9475","authenticated-orcid":true,"given":"Marc L.","family":"Reitman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,16]]},"reference":[{"issue":"3","key":"pone.0243986.ref001","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1152\/physrev.00049.2017","article-title":"Pharmacology of Adenosine Receptors: The State of the Art","volume":"98","author":"PA Borea","year":"2018","journal-title":"Physiol Rev"},{"issue":"4","key":"pone.0243986.ref002","doi-asserted-by":"crossref","first-page":"C799","DOI":"10.1152\/ajpcell.1989.256.4.C799","article-title":"Turnover of adenosine in plasma of human and dog blood","volume":"256","author":"GH Moser","year":"1989","journal-title":"Am J Physiol"},{"issue":"3","key":"pone.0243986.ref003","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s00109-013-1101-6","article-title":"Adenosine\u2014a physiological or pathophysiological agent?","volume":"92","author":"BB Fredholm","year":"2014","journal-title":"J Mol Med (Berl)"},{"issue":"1","key":"pone.0243986.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/pr.110.003285","article-title":"International Union of Basic and Clinical Pharmacology. 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