{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:38:36Z","timestamp":1788910716114,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T00:00:00Z","timestamp":1721088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute on Drug Abuse","award":["P30DA033934"],"award-info":[{"award-number":["P30DA033934"]}]},{"name":"National Institute on Drug Abuse","award":["UH3DA050311"],"award-info":[{"award-number":["UH3DA050311"]}]},{"name":"National Institute on Drug Abuse","award":["UG3DA054785"],"award-info":[{"award-number":["UG3DA054785"]}]},{"name":"National Institute on Drug Abuse","award":["R61NS133217"],"award-info":[{"award-number":["R61NS133217"]}]},{"name":"National Institute on Neurological Disorders and Stroke","award":["P30DA033934"],"award-info":[{"award-number":["P30DA033934"]}]},{"name":"National Institute on Neurological Disorders and Stroke","award":["UH3DA050311"],"award-info":[{"award-number":["UH3DA050311"]}]},{"name":"National Institute on Neurological Disorders and Stroke","award":["UG3DA054785"],"award-info":[{"award-number":["UG3DA054785"]}]},{"name":"National Institute on Neurological Disorders and Stroke","award":["R61NS133217"],"award-info":[{"award-number":["R61NS133217"]}]},{"name":"National Institutes of Health Intramural Research Programs of NIDA and NIAAA","award":["P30DA033934"],"award-info":[{"award-number":["P30DA033934"]}]},{"name":"National Institutes of Health Intramural Research Programs of NIDA and NIAAA","award":["UH3DA050311"],"award-info":[{"award-number":["UH3DA050311"]}]},{"name":"National Institutes of Health Intramural Research Programs of NIDA and NIAAA","award":["UG3DA054785"],"award-info":[{"award-number":["UG3DA054785"]}]},{"name":"National Institutes of Health Intramural Research Programs of NIDA and NIAAA","award":["R61NS133217"],"award-info":[{"award-number":["R61NS133217"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>We recently developed a series of nalfurafine analogs (TK10, TK33, and TK35) that may serve as non-addictive candidate analgesics. These compounds are mixed-action agonists at the kappa and delta opioid receptors (KOR and DOR, respectively) and produce antinociception in a mouse warm-water tail-immersion test while failing to produce typical mu opioid receptor (MOR)-mediated side effects. The warm-water tail-immersion test is an assay of pain-stimulated behavior vulnerable to false-positive analgesic-like effects by drugs that produce motor impairment. Accordingly, this study evaluated TK10, TK33, and TK35 in a recently validated assay of pain-related behavioral depression in mice that are less vulnerable to false-positive effects. For comparison, we also evaluated the effects of the MOR agonist\/analgesic hydrocodone (positive control), the neurokinin 1 receptor (NK1R) antagonist aprepitant (negative control), nalfurafine as a selective KOR agonist, SNC80 as a selective DOR agonist, and a nalfurafine\/SNC80 mixture. Intraperitoneal injection of dilute lactic acid (IP lactic acid) served as a noxious stimulus to depress vertical and horizontal locomotor activity in male and female ICR mice. IP lactic acid-induced locomotor depression was alleviated by hydrocodone but not by aprepitant, nalfurafine, SNC80, the nalfurafine\/SNC80 mixture, or the KOR\/DOR agonists. These results suggest that caution is warranted in advancing mixed-action KOR\/DOR agonists as candidate analgesics.<\/jats:p>","DOI":"10.3390\/molecules29143331","type":"journal-article","created":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T09:46:57Z","timestamp":1721123217000},"page":"3331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Effects of Selective and Mixed-Action Kappa and Delta Opioid Receptor Agonists on Pain-Related Behavioral Depression in Mice"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8471-645X","authenticated-orcid":false,"given":"S. Stevens","family":"Negus","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9845-7118","authenticated-orcid":false,"given":"Celsey M.","family":"St. Onge","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young K.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengchu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1147-9147","authenticated-orcid":false,"given":"Kenner C.","family":"Rice","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8934-7016","authenticated-orcid":false,"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1001\/jama.2021.13300","article-title":"The Helping to End Addiction Long-term (HEAL) Initiative of the National Institutes of Health","volume":"326","author":"Baker","year":"2021","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3608","DOI":"10.1021\/acschemneuro.2c00526","article-title":"Characterization of a Potential KOR\/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure-Activity Relationship Study on Nalfurafine Analogues","volume":"13","author":"Li","year":"2022","journal-title":"ACS Chem. 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