Synergistic blockade of alcohol escalation drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone

Abstract

Mesyl Salvinorin B (MSB) is a potent selective kappa opioid receptor (KOP-r) agonist that has potential for development as an anti-psychostimulant agent with fewer side-effects (e.g., sedation, depression and dysphoria) than classic KOP-r agonists. However, no such study has been done on alcohol. We investigated whether MSB alone or in combination with naltrexone (mu-opioid receptor antagonist) altered voluntary alcohol drinking in both male and female mice. Mice, subjected to 3 weeks of chronic escalation drinking (CED) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference. We found that single, acute administration of MSB dose-dependently reduced alcohol intake and preference in mice after 3-week CED. The effect was specific to alcohol, as shown by the lack of any effect of MSB on sucrose or saccharin intake. We also used the drinking-in-the-dark (DID) model with limited access (4 h/day) to evaluate the pharmacological effect of MSB after 3 weeks of DID. However, MSB had no effect on alcohol drinking after 3-week DID. Upon investigation of potential synergistic effects between naltrexone and MSB, we found that acute administration of a combination of MSB and naltrexone reduced alcohol intake profoundly after 3-week CED at doses lower than those individual effective doses. Repeated administrations of this combination showed less tolerance development than repeated MSB alone. Our study suggests that the novel KOP-r agonist MSB both alone and in combination with naltrexone shows potential in alcoholism treatment models.

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

“…KOP-r/dynorphin activation is associated with the negative reinforcement aspects of alcohol addictions. It has been found that selective blockade of KOP-r attenuates excessive drinking, stress or cue -induced alcohol-seeking in mice and rats [Walker and Koob, 2008;Sperling et al, 2010;Deehan et al, 2012;Schank et al, 2012;Funk et al, 2014;Rorick-Kehn et al, 2014;Anderson et al, 2016;Zhou et al, 2017a] (but also see Mitchell et al, 2005;Sirohi et al, 2016). In line with these pharmacological results, alcohol drinking is decreased in KOP-r knockout mice [Kovacs et al, 2005].…”

“…There are sex differences in dynorphin/KOP-r systems [Chartoff and Mavrikaki, 2015] and alcohol drinking behavior [Becker and Koob, 2016]. Indeed, we observe a reduction of alcohol drinking with the selective KOP-r antagonist nor-binaltorphimine (nor-BNI, slow onset and extraordinarily long-lasting effect [Horan et al, 1992]) in male mice, while the same nor-BNI treatment has no effect on alcohol drinking in female mice [Zhou et al, 2017a].…”

“…Recently, there is rapidly growing research into the identification of functionally selective (biased) KOP-r full agonists or partial agonists for the development of anti-addictive compounds [Maillet et al, 2015;Simonson et al, 2015;White et al, 2015;Brust et al, 2016;Schattauer et al, 2017;Townsend et al, 2017;Zhou et al, 2017a]. For a good example, Mesyl Salvinorin B (MSB), an analogue of salvinorin A, is a potent KOP-r full agonist with fewer side effects (sedation and dysphoria) compared to other "classic" KOP-r agonists [Simonson et al, 2015;Zhou et al, 2017a].…”

“…For a good example, Mesyl Salvinorin B (MSB), an analogue of salvinorin A, is a potent KOP-r full agonist with fewer side effects (sedation and dysphoria) compared to other "classic" KOP-r agonists [Simonson et al, 2015;Zhou et al, 2017a]. We have further examined the pharmacological effects of MSB on excessive or "relapse" drinking in mice, to determine its potential for development as an antirelapse compound for alcoholism.…”

“…We have further examined the pharmacological effects of MSB on excessive or "relapse" drinking in mice, to determine its potential for development as an antirelapse compound for alcoholism. Acute administration of MSB significantly reduces both excessive drinking in an IA model and "relapse" drinking in a mouse ADE model in a dosedependent manner [Zhou et al, 2017a[Zhou et al, , 2017d. Nalfurafine (clinically available G-biased KOP-r agonist) with few side effects [Schattauer et al, 2017], also decreases excessive alcohol drinking in mice [Zhou et al, 2018b].…”