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. 2019 Jun;43(6):1077-1090.
doi: 10.1111/acer.14033. Epub 2019 May 2.

Combination of Clinically Utilized Kappa-Opioid Receptor Agonist Nalfurafine With Low-Dose Naltrexone Reduces Excessive Alcohol Drinking in Male and Female Mice

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Free PMC article

Combination of Clinically Utilized Kappa-Opioid Receptor Agonist Nalfurafine With Low-Dose Naltrexone Reduces Excessive Alcohol Drinking in Male and Female Mice

Yan Zhou et al. Alcohol Clin Exp Res. .
Free PMC article

Abstract

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.

Conflict of interest statement

Conflict of interest: All authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Effects of single administration of nalfurafine (NFF, 10ug/kg) on alcohol intake (A), water intake (B), and preference ratio (C) in male and female mice after 3-week chronic intermittent access drinking. (1) Control groups: males (n=7) and females (n=14) received saline injection (i.p.); and (2) NFF groups: males (n=8) and females (n=14) received one NFF injection (i.p.) 30 min before the drinking test. Alcohol and water intake values were recorded after 4, 8 and 24 hours. * p<0.05 vs. control at the same time point. Data in table are presented as mean+SEM.
Figure 2
Figure 2
Dose response of single administration of nalfurafine (NFF, 0, 0.3, 1, 3 or 10 ug/kg) alone or combined with naltrexone (NTN, 0, 0.3 or 1 mg/kg) on decreasing alcohol intake (A) and alcohol preference ratio (B) in male and female mice after 3-week chronic intermittent access drinking. Data were collected at the first 4-hour recording time on the baseline and the testing day (24 hours later) and are expressed as a percentage of baseline intake to account for the differences in baseline that contribute to variation between experiments (n=6–14). *p<0.05 or **p<0.01 vs. control (both NFF and NTN at 0 mg/kg); #p<0.05 between treatment groups. Data in table are presented as mean+SEM.
Figure 3
Figure 3
Pretreatment with selective KOP-r antagonist nor-BNI (2.5mg/kg) blocks the effect of single nalfurafine (NFF, 10ug/kg) on decreasing alcohol intake (A) and preference ration (B), but not water intake (C) in male mice (n=6–8). *p<0.05 vs. vehicle control with the same pretreatment. Data in table are presented as mean+SEM.
Figure 4
Figure 4
Effects of single nalfurafine (NFF) administration at 1ug/kg combined with naltrexone (NTN, 1mg/kg) on alcohol intake (A), water intake (B) and preference ratio (C) in male (left) and female (right) mice (n=6–8) after 3-week chronic intermittent access drinking. Control groups: mice received one saline (i.p.) followed by saline. Test groups: mice received one NFF injection (1ug/kg, i.p.) followed by one NTN injection (1mg/kg, i.p.) before the alcohol drinking test. Alcohol and water intake were recorded after 4, 8 and 24 hours. * p<0.05 vs. control at the same time point. Data in table are presented as mean+SEM.
Figure 5
Figure 5
Effects of repeated administrations of nalfurafine (10ug/kg) on alcohol intake (A) and preference ratio (B) after 3-week intermittent access drinking in male mice (n=6). *p<0.05 vs. the baseline. Data in table are presented as mean+SEM.
Figure 6
Figure 6
Genotype differences in the effects of acute nalfurafine (1ug/kg) on alcohol intake (A), preference ratio (B) and water intake (C) after 3-week intermittent access drinking at 4 hours in male (left) and female (right) nPE mice (n=6). In each sex, mice were assigned to one of four groups: (1) nPE+/+ with vehicle; (2) nPE+/+ with 1ug/kg nalfurafine; (3) nPE−/− with vehicle; and (4) nPE−/− with 1ug/kg nalfurafine. Genotype difference: *p<0.05 vs. nPE+/+ mice after the same treatment; Nalfurafine effect: #p<0.05 vs. vehicle control in the same genotype. Data in table are presented as mean+SEM.
Figure 7
Figure 7
No Effect of single administration of nalfurafine (3 or 10ug/kg) on alcohol intake after 3-week drinking-in-the-dark (DID) in male (left) or female (right) mice (n=8). Data in table are presented as mean+SEM.

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