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

Yan Zhou, Rachel Saylor Crowley, Konrad Ben, Thomas E. Prisinzano, Mary Jeanne Kreek

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish
Pages (from-to)75-86
Number of pages12
JournalBrain Research
StatePublished - May 1 2017

Bibliographical note

Funding Information:
This work was supported by NIH AA021970 (YZ), DA018151 (TEP), GM008545 (RSC) and AFPE Pre-Doctoral Fellowship in Pharmaceutical Sciences (to RSC), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (MJK). The authors would like to thank Benjamin Neuenswander for his technical assistance in the microsomal stability studies. Special thanks to Dr. R. Schaefer for providing his comments and corrections on the manuscript.

Publisher Copyright:
© 2017 Elsevier B.V.


  • Alcohol escalation drinking
  • Combined therapy
  • KOP-r
  • Mesyl Salvinorin B
  • Naltrexone

ASJC Scopus subject areas

  • Neuroscience (all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology


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