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Article
Pharmacology and Anti-Addiction Effects of the Novel κ Opioid Receptor Agonist Mesyl Sal B, a Potent and Long-Acting Analogue of Salvinorin A
British Journal of Pharmacology
  • B. Simonson, Victoria University of Wellington
  • A. S. Morani, Victoria University of Wellington
  • A. W. M. Ewald, Victoria University of Wellington
  • L. Walker, Victoria University of Wellington
  • N. Kumar, Victoria University of Wellington
  • Denise S. Simpson, Cedarville University
  • J. H. Miller, Victoria University of Wellington
  • T. E. Prisinzano, University of Kansas
  • B. M. Kivell, Victoria University of Wellington
Document Type
Article
Publication Date
1-1-2015
DOI
http://dx.doi.org/10.1111/bph.12692
PubMed ID
24641310
PubMed Central® ID
PMC4292965
Abstract
Background and Purpose: 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. Experimental Approach: 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. Key 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 and Implications: 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.
Keywords
  • Salvia divinorum,
  • addiction,
  • cocaine self-administration,
  • dopamine transporter,
  • drug seeking,
  • nociception,
  • salvinorin A,
  • κ opioid receptor
Citation Information
B. Simonson, A. S. Morani, A. W. M. Ewald, L. Walker, et al.. "Pharmacology and Anti-Addiction Effects of the Novel κ Opioid Receptor Agonist Mesyl Sal B, a Potent and Long-Acting Analogue of Salvinorin A" British Journal of Pharmacology Vol. 172 Iss. 2 (2015) p. 515 - 531 ISSN: 1476-5381
Available at: http://works.bepress.com/denise_simpson/28/