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SalvinorinA<\/jats:styled-content>, isolated from the plantS<\/jats:italic><\/jats:styled-content>alvia divinorum,<\/jats:italic>and its semi\u2010synthetic analogues have been shown to have potentKOP<\/jats:styled-content>receptor agonist activity and may induce a unique response with similar anticocaine addiction effects as the classicKOP<\/jats:styled-content>receptor agonists, but with a different side effect profile.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>We evaluated the duration of effects ofM<\/jats:styled-content>esylS<\/jats:styled-content>alB<\/jats:styled-content>\u2005in vivo<\/jats:italic>utilizing antinociception assays and screened for cocaine\u2010prime induced cocaine\u2010seeking behaviour in self\u2010administering rats to predict anti\u2010addiction effects. Cellular transporter uptake assays andin vitro<\/jats:italic>voltammetry were used to assess modulation of dopamine transporter (DAT<\/jats:styled-content>) function and to investigate transporter trafficking and kinase signalling pathways modulated byKOP<\/jats:styled-content>receptor agonists.<\/jats:p><\/jats:sec>Key Results<\/jats:title>M<\/jats:styled-content>esylS<\/jats:styled-content>alB<\/jats:styled-content>had a longer duration of action thanSalA<\/jats:styled-content>, had anti\u2010addiction properties and increasedDAT<\/jats:styled-content>functionin vitro<\/jats:italic>in aKOP<\/jats:styled-content>receptor\u2010dependent andPertussis<\/jats:italic>toxin\u2010sensitive manner. These effects onDAT<\/jats:styled-content>function requiredERK<\/jats:styled-content>1\/2 activation. We identified differences betweenM<\/jats:styled-content>esylS<\/jats:styled-content>alB<\/jats:styled-content>andSalA<\/jats:styled-content>, withM<\/jats:styled-content>esylS<\/jats:styled-content>alB<\/jats:styled-content>increasing theV<\/jats:italic><\/jats:styled-content>max<\/jats:sub>of dopamine uptake without altering cell\u2010surface expression ofDAT<\/jats:styled-content>.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>SalA<\/jats:styled-content>analogues, such asM<\/jats:styled-content>esylS<\/jats:styled-content>alB<\/jats:styled-content>, have potential for development as anticocaine agents. Further tests are warranted to elucidate the mechanisms by which the novel salvinorin\u2010based neoclerodane diterpeneKOP<\/jats:styled-content>receptor ligands produce both anti\u2010addiction and adverse side effects.<\/jats:p><\/jats:sec>Linked Articles<\/jats:title>This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. 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