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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,8,12]]},"abstract":"<jats:p>\n                    Noradrenaline is a major monoaminergic neurotransmitter involved in pain modulation through an \u03b12A-adrenergic receptor. Hence, \u03b12-adrenergic agonists such as clonidine and dexmedetomidine exhibit analgesic and opioid-sparing effects. However, their use is restricted to hospital settings due to potential risks of acute hypertension\/hypotension and bradycardia. Here, we report that (\n                    <jats:italic toggle=\"yes\">Z<\/jats:italic>\n                    )-1-(3-ethyl-5-fluorobenzo[\n                    <jats:italic toggle=\"yes\">d<\/jats:italic>\n                    ] thiazol-2(3\n                    <jats:italic toggle=\"yes\">H<\/jats:italic>\n                    )-ylidene)propan-2-one [adrenergic inducer of analgesia (ADRIANA)], a newly identified \u03b12B subtype-specific antagonist, specifically promotes noradrenaline release in the murine spinal dorsal horn and produces analgesic effects by stimulating the \u03b12A-dependent pain inhibitory pathway. Orally administered ADRIANA has potent analgesic effects in several nociceptive pain models of mice and nonhuman primates without cardiovascular effects. Mice with genetic loss of the \u03b12B adrenoceptor showed normal responses to mechanical pain, but the analgesic effect of ADRIANA was not significantly detected. These findings reveal that the \u03b12B adrenoceptor is a promising target for nonopioid analgesics through the activation of the \u03b12A-dependent descending pathway.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2500006122","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T15:35:16Z","timestamp":1754580916000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["Discovery and development of an oral analgesic targeting the \u03b12B adrenoceptor"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3110-1387","authenticated-orcid":false,"given":"Masayasu","family":"Toyomoto","sequence":"first","affiliation":[{"name":"Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University","place":["Kyoto, Japan"]},{"name":"Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University","place":["Kyoto, Japan"]},{"name":"Department of Drug Discovery for Intractable Diseases, Graduate School of Medicine, Kyoto University","place":["Kyoto, Japan"]},{"name":"Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University","place":["Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4001-6771","authenticated-orcid":false,"given":"Takashi","family":"Kurihara","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University","place":["Kagoshima, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacotherapy, School of Pharmaceutical Sciences, Wakayama Medical University","place":["Wakayama, Japan"]},{"name":"Department of Clinical Pharmacology and Therapeutics, 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University of Tokyo","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7270-351X","authenticated-orcid":false,"given":"Takamitsu","family":"Hosoya","sequence":"additional","affiliation":[{"name":"Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1193-7571","authenticated-orcid":false,"given":"Masatoshi","family":"Hagiwara","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University","place":["Kyoto, Japan"]},{"name":"Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University","place":["Kyoto, 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and safety of sedation with dexmedetomidine in critical care patients: A meta-analysis of randomized controlled trials","volume":"35","author":"Constantin J. 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