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Combination of Clinically Utilized Kappa-Opioid Receptor Agonist Nalfurafine With Low-Dose Naltrexone... (Abstract)
Combination of Clinically Utilized Kappa-Opioid Receptor Agonist Nalfurafine With Low-Dose Naltrexone Reduces Excessive Alcohol Drinking in Male and Female Mice
Alcohol Clin Exp Res
Background: Nalfurafine is the first clinically approved kappa-opioid receptor (KOP-r) agonist as an antipruritus drug with few side effects in humans (e.g., sedation, depression, and dysphoria). No study, however, has been done using nalfurafine on alcohol drinking in rodents or humans.
Methods: We investigated whether nalfurafine alone or in combination with mu-opioid receptor (MOP-r) antagonist naltrexone changed excessive alcohol drinking in male and female C57BL/6J (B6) mice subjected to a chronic intermittent-access drinking paradigm (2-bottle choice, 24-hour access every other day) for 3 weeks. Neuronal proopiomelanocortin enhancer (nPE) knockout mice with brain-specific deficiency of beta-endorphin (endogenous ligand of MOP-r) were used as a genetic control for the naltrexone effects.
Results: Single administration of nalfurafine decreased alcohol intake and preference in both male and female B6 mice in a dose-dependent manner. Pretreatment with nor-BNI (a selective KOP-r antagonist) blocked the nalfurafine effect on alcohol drinking, indicating a KOP-r-mediated mechanism. Pharmacological effects of a 5-dosing 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-like (sucrose preference test), anxiety-like (elevated plus maze test), or dysphoria-like (conditioned place aversion test) behaviors, suggesting that nalfurafine had few side effects. Investigating synergistic effects between low-dose 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 nPE-/- mice, suggesting independent mechanisms by which nalfurafine and naltrexone reduced alcohol drinking.
Conclusion: The clinically utilized KOP-r agonist nalfurafine in combination with low-dose naltrexone has potential in alcoholism treatment.
Keywords: Combined Therapy; Excessive Alcohol Drinking; Kappa-Opioid Receptor; Nalfurafine; Naltrexone; nPE Knockout.