Pharmaceutical Sciences Faculty Publications

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

Document Type

Article

Publication Date

1-2015

Journal Title

British Journal of Pharmacology

ISSN

1476-5381

Volume

172

Issue

2

First Page

515

Last Page

531

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