title: Pharmacology and anti-addiction effects of the novel κ opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A.
abstract: OBJECTIVE
  Acute activation of κ opioid (KOP) receptors results in anticocaine-like effects, but adverse effects, such as dysphoria, aversion, sedation and depression, limit their clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi-synthetic analogues have been shown to have potent KOP receptor agonist activity and may induce a unique response with similar anticocaine addiction effects as the classic KOP receptor agonists, but with a different side effect profile.
  
  
  METHODS
  We evaluated the duration of effects of Mesyl Sal B in vivo utilizing antinociception assays and screened for cocaine-prime induced cocaine-seeking behaviour in self-administering rats to predict anti-addiction effects. Cellular transporter uptake assays and in vitro voltammetry were used to assess modulation of dopamine transporter (DAT) function and to investigate transporter trafficking and kinase signalling pathways modulated by KOP receptor agonists.
  
  
  RESULTS
  Mesyl Sal B had a longer duration of action than SalA, had anti-addiction properties and increased DAT function in vitro in a KOP receptor-dependent and Pertussis toxin-sensitive manner. These effects on DAT function required ERK1/2 activation. We identified differences between Mesyl Sal B and SalA, with Mesyl Sal B increasing the Vmax of dopamine uptake without altering cell-surface expression of DAT.
  
  
  CONCLUSIONS
  SalA analogues, such as Mesyl Sal B, have potential for development as anticocaine agents. Further tests are warranted to elucidate the mechanisms by which the novel salvinorin-based neoclerodane diterpene KOP receptor ligands produce both anti-addiction and adverse side effects.
  
  
  BACKGROUND
  This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
authors.affiliation: School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: B
authors.initials: B
authors.lastname: Simonson
authors.forename: A S
authors.initials: AS
authors.lastname: Morani
authors.forename: A W M
authors.initials: AW
authors.lastname: Ewald
authors.forename: L
authors.initials: L
authors.lastname: Walker
authors.forename: N
authors.initials: N
authors.lastname: Kumar
authors.forename: D
authors.initials: D
authors.lastname: Simpson
authors.forename: J H
authors.initials: JH
authors.lastname: Miller
authors.forename: T E
authors.initials: TE
authors.lastname: Prisinzano
authors.forename: B M
authors.initials: BM
authors.lastname: Kivell
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology* / Q000627:therapeutic use*; D045785:Diterpenes, Clerodane; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D058999:Drug-Seeking Behavior / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008698:Mesylates / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D012646:Self Administration
chemical_list: D004224:Diterpenes; D045785:Diterpenes, Clerodane; D050483:Dopamine Plasma Membrane Transport Proteins; D008698:Mesylates; D017473:Receptors, Opioid, kappa; C000600932:mesyl salvinorin B; D003042:Cocaine
keywords: Salvia divinorum; addiction; cocaine self-administration; dopamine transporter; drug seeking; nociception; salvinorin A; κ opioid receptor