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No study, however, has been done using nalfurafine on alcohol drinking in rodents or humans.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated whether nalfurafine alone or in combination with mu\u2010opioid receptor (<jats:styled-content style=\"fixed-case\">MOP<\/jats:styled-content>\u2010r) antagonist naltrexone changed excessive alcohol drinking in male and female C57<jats:styled-content style=\"fixed-case\">BL<\/jats:styled-content>\/6J (B6) mice subjected to a chronic intermittent\u2010access drinking paradigm (2\u2010bottle choice, 24\u2010hour access every other day) for 3\u00a0weeks. Neuronal proopiomelanocortin enhancer (<jats:styled-content style=\"fixed-case\">nPE<\/jats:styled-content>) knockout mice with brain\u2010specific deficiency of beta\u2010endorphin (endogenous ligand of <jats:styled-content style=\"fixed-case\">MOP<\/jats:styled-content>\u2010r) were used as a genetic control for the naltrexone effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Single administration of nalfurafine decreased alcohol intake and preference in both male and female B6 mice in a dose\u2010dependent manner. Pretreatment with nor\u2010<jats:styled-content style=\"fixed-case\">BNI<\/jats:styled-content> (a selective <jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>\u2010r antagonist) blocked the nalfurafine effect on alcohol drinking, indicating a <jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>\u2010r\u2010mediated mechanism. Pharmacological effects of a 5\u2010dosing nalfurafine regimen were further evaluated: The repeated nalfurafine administrations decreased alcohol consumption without showing any blunted effects, suggesting nalfurafine did not develop a tolerance after the multidosing regimen tested. Nalfurafine did not produce any sedation (spontaneous locomotor activity), anhedonia\u2010like (sucrose preference test), anxiety\u2010like (elevated plus maze test), or dysphoria\u2010like (conditioned place aversion test) behaviors, suggesting that nalfurafine had few side effects. Investigating synergistic effects between low\u2010dose naltrexone and nalfurafine, we found that single combinations of nalfurafine and naltrexone, at doses lower than individual effective dose, profoundly decreased excessive alcohol intake in both sexes. The effect of nalfurafine on decreasing alcohol consumption was confirmed in <jats:styled-content style=\"fixed-case\">nPE<\/jats:styled-content>\u2212\/\u2212 mice, suggesting independent mechanisms by which nalfurafine and naltrexone reduced alcohol drinking.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The clinically utilized <jats:styled-content style=\"fixed-case\">KOP<\/jats:styled-content>\u2010r agonist nalfurafine in combination with low\u2010dose naltrexone has potential in alcoholism treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14033","type":"journal-article","created":{"date-parts":[[2019,3,25]],"date-time":"2019-03-25T17:16:28Z","timestamp":1553534188000},"page":"1077-1090","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Combination of Clinically Utilized Kappa\u2010Opioid Receptor Agonist Nalfurafine With Low\u2010Dose Naltrexone Reduces Excessive Alcohol 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