{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:43:53Z","timestamp":1760147033688,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T00:00:00Z","timestamp":1672704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["81960624","2021LQGR01","20JR10RN827","21JR1RA078","2020-RC-90","lzujbky-2021-kb36"],"award-info":[{"award-number":["81960624","2021LQGR01","20JR10RN827","21JR1RA078","2020-RC-90","lzujbky-2021-kb36"]}]},{"name":"Science and Technology Program of Gansu Province","award":["81960624","2021LQGR01","20JR10RN827","21JR1RA078","2020-RC-90","lzujbky-2021-kb36"],"award-info":[{"award-number":["81960624","2021LQGR01","20JR10RN827","21JR1RA078","2020-RC-90","lzujbky-2021-kb36"]}]},{"name":"the Science and Technology Project of Lanzhou Science and Technology Bureau","award":["81960624","2021LQGR01","20JR10RN827","21JR1RA078","2020-RC-90","lzujbky-2021-kb36"],"award-info":[{"award-number":["81960624","2021LQGR01","20JR10RN827","21JR1RA078","2020-RC-90","lzujbky-2021-kb36"]}]},{"name":"the Fundamental Research Funds for the Central Universities","award":["81960624","2021LQGR01","20JR10RN827","21JR1RA078","2020-RC-90","lzujbky-2021-kb36"],"award-info":[{"award-number":["81960624","2021LQGR01","20JR10RN827","21JR1RA078","2020-RC-90","lzujbky-2021-kb36"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Pain is a common clinical symptom among patients. Although various opioid analgesics have been developed, their side effects hinder their application. This study aimed to develop a novel opioid analgesic, HAGD (H-Tyr-D-AIa-GIy-Phe-NH2), with limited side effects. In vivo studies on mouse models as well as in vitro studies on Chinese hamster ovary (CHO) cells expressing human mu, delta, or kappa opioid receptors (CHOhMOP, CHOhDOP, and CHOhKOP, respectively) and human sperm were conducted. Compared with subcutaneous morphine (10 mg\/kg), subcutaneous HAGD (10 mg\/kg) produced equipotent or even greater antinociception with a prolonged duration by activating mu\/delta opioid receptors in preclinical mouse pain models. The analgesic tolerance, rewarding effects (i.e., conditioned place preference and acute hyperlocomotion), and gastrointestinal transit inhibition of HAGD were significantly reduced compared with those of morphine. Both HAGD and morphine exhibited a withdrawal response and had no impacts on motor coordination. In CHOhMOP and CHOhDOP, HAGD showed specific and efficient intracellular Ca2+ stimulation. HAGD had minimal impact on human sperm motility in vitro, whereas 1 \u00d7 10\u22127 and 1 \u00d7 10\u22128 mol\/L of morphine significantly declined sperm motility at 3.5 h. Overall, HAGD may serve as a promising antinociceptive compound.<\/jats:p>","DOI":"10.3390\/molecules28010427","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T02:54:55Z","timestamp":1672800895000},"page":"427","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Novel Multi-Target Mu\/Delta Opioid Receptor Agonist, HAGD, Produced Potent Peripheral Antinociception with Limited Side Effects in Mice and Minimal Impact on Human Sperm Motility In Vitro"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3446-1289","authenticated-orcid":false,"given":"Fangfang","family":"Li","sequence":"first","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"},{"name":"Key Laboratory for Reproductive Medicine and Embryo of Gansu, Gansu International Scientific and Technological Cooperation Base of Reproductive Medicine Transformation Application, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Yue","sequence":"additional","affiliation":[{"name":"Key Laboratory for Reproductive Medicine and Embryo of Gansu, Gansu International Scientific and Technological Cooperation Base of Reproductive Medicine Transformation Application, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory for Reproductive Medicine and Embryo of Gansu, Gansu International Scientific and Technological Cooperation Base of Reproductive Medicine Transformation Application, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Biao","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiqing","family":"Wang","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"},{"name":"Key Laboratory for Reproductive Medicine and Embryo of Gansu, Gansu International Scientific and Technological Cooperation Base of Reproductive Medicine Transformation Application, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuehong","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"},{"name":"Key Laboratory for Reproductive Medicine and Embryo of Gansu, Gansu International Scientific and Technological Cooperation Base of Reproductive Medicine Transformation Application, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/nrd3226","article-title":"Pain market","volume":"9","author":"Melnikova","year":"2010","journal-title":"Nat. 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