期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 172, 期 2, 页码 515-531出版社
WILEY
DOI: 10.1111/bph.12692
关键词
salvinorin A; Salvia divinorum; cocaine self-administration; drug seeking; opioid receptor; addiction; nociception; dopamine transporter
资金
- Health Research Council of New Zealand
- Neurological Foundation of New Zealand
- Wellington Medical Research Foundation
- Lottery Health
- National Institutes of Health, USA [NIDA 018151]
- Victoria University of Wellington, New Zealand
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA018151] Funding Source: NIH RePORTER
Background and PurposeAcute activation of 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 ApproachWe evaluated the duration of effects of Mesyl Sal Bin 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 ResultsMesyl 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 V-max of dopamine uptake without altering cell-surface expression of DAT. Conclusions and ImplicationsSalA 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. Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit
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