Effects of mesyl salvinorin B alone and in combination with naltrexone on alcohol deprivation effect in male and female mice

Abstract

Alcohol relapse plays a major role in alcohol dependence and is an important focus for the treatment of alcoholism. The alcohol deprivation effect (ADE) is a widely used paradigm in rodents to model the relapse episodes that occur in human alcoholics. Mesyl Salvinorin B (MSB) is a potent and selective kappa opioid receptor (KOP-r) full agonist, with fewer side effects (e.g., sedation or anhedonia) than classic KOP-r full agonists and a longer duration of action in mice than the structurally similar salvinorin A. We have recently found that MSB prevents cocaine seeking in a rat self-administration model and reduces excessive alcohol drinking in a mouse escalation model via a KOP-r-mediated mechanism. Here, we further investigated whether MSB alone (0.3-3 mg/kg) or in combination with naltrexone (mu-opioid receptor antagonist at 1 mg/kg) altered alcohol "relapse" drinking using a mouse ADE paradigm. Both male and female mice, exposed to 3-week intermittent access alcohol drinking in a two-bottle choice paradigm with 24-h access every other day, developed excessive alcohol intake and then displayed pronounced ADE after 1-week abstinence. Acute administration of MSB prevented the ADE at 3 mg/kg in both male and female mice. Upon investigation of potential synergistic effects between naltrexone and MSB, we found that acute administration of a combination of MSB (0.3 mg/kg) and naltrexone (1 mg/kg) reduced the ADE at doses lower than those individual effective doses, with no sex difference. Our study suggests that the KOP-r full agonist MSB both alone and in combination with naltrexone shows potential in alcohol "relapse" treatment models.

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

“…Like the previous reports (Zhou et al., , 2018a), naltrexone at this dose range (0.3 to 3 mg/kg) had no effect on sucrose (4 to 16%) or saccharin (0.1 to 0.4%) consumption in either males or females (data not shown).…”

“…Power analyses were performed to determine the number of mice required to provide statistically significant results, based on the levels of differences reported before (Zhou et al., , 2018a). In the experiments with single nalfurafine, naltrexone, their combinations, or nor‐BNI, the group differences in alcohol (or sucrose, saccharin) intake, water intake, total fluid, and preference ratio in each sex were analyzed using 2‐way ANOVA with repeated measures for treatment (vehicle vs. drug) and for time interval (0 to 4, 5 to 8 vs. 9 to 24).…”

“…However, most “classic” KOP‐r agonists like U50,488H and U69,593 induce strong sedation and dysphoria‐like behavior, and such side effects limit their clinical use potential (e.g., Morani et al., ). Mesyl salvinorin B (MSB), a novel selective KOP‐r agonist with few side effects, has been recently found to attenuate drug intake and drug‐seeking behaviors (Simonson et al., ; Zhou et al., , 2018a). Together, these findings provide support for the important involvement of the KOP‐r systems in the development of alcohol consumption and addiction.…”

“…For this purpose, we evaluated the pharmacological effect of nalfurafine using a chronic intermittent‐access (IA) drinking model, in which both male and female mice had access to voluntary alcohol drinking for 3 weeks in a 2‐bottle free‐choice paradigm with alcohol intake every other day. Of importance, the mice exposed to this IA paradigm quickly developed high alcohol intake (15 to 25 g/kg/d), which constitutes an appropriate rodent model for studying excessive alcohol consumption (Hwa et al., ; Zhou et al., , 2018a). To determine the potential side effects, we further tested whether nalfurafine induced any anhedonia‐like behavior in a sucrose or saccharin drinking test, anxiety‐like behavior in an elevated plus maze test, dysphoria‐like behavior in a conditioned place aversion test, or sedation in a spontaneous locomotor activity test.…”

Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant

“…However, it mitigated cocaine-induced hyperactivity and behavioral sensitization, without affecting aversion, sedation, anxiety, or learning and memory impairment in rats [320]. Additionally, mesyl salvinorin B alone or associated with naltrexone prevented alcohol-induced deprivation effect in mice [321], which could represent an alternative tool for treatment of alcoholism in humans. Other salvinorin A analogues, such as p38, could also be effective for the treatment of gastrointestinal inflammation, since it demonstrated anti-inflammatory and analgesic effects in an experimental model of colitis [322].…”