Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats

Abstract

Background and rationale Research interests regarding the psychopharmacology of salvinorin A have been motivated by the recreational use and widespread media focus on the hallucinogenic plant, Salvia divinorum. Additionally, kappa opioid (KOP) receptor ligands may have therapeutic potential in the treatment of some neuropsychiatric conditions, including drug dependence and mood disorders. Salvinorin A is a selective KOP agonist, but only a few studies have explored the discriminative stimulus effects of this compound. Objective This study compared the discriminative stimulus effects of salvinorin A and two synthetic derivatives of salvinorin B to the KOP agonists, U69,593 and U50,488. Materials and methods Sixteen male Sprague-Dawley rats trained to discriminate U69,593 (0.13 mg/kg, s.c., N=8) or U50,488 (3.0 mg/kg, i.p., N=8) under a fixed-ratio 20 schedule of food reinforcement were administered substitution tests with salvinorin A (0.125-3.0 mg/kg, i.p.). The animals trained to discriminate U69,593 were also administered substitution tests with salvinorin B ethoxymethyl ether (0.005-0.10 mg/kg, i.p.) and salvinorin B methoxymethyl ether (0.03-0.10 mg/kg, i.p.). Another eight rats were trained to discriminate 2.0 mg/kg salvinorin A and tested with U69,593 (0.04-0.32 mg/kg) and U50,488 (0.4-3.2 mg/kg). Results Salvinorin A and both synthetic derivatives of salvinorin B substituted completely for U69,593. Additionally, cross-generalization was observed between salvinorin A and both KOP agonists.Conclusion These findings support previous reports indicating that the discriminative stimulus effects of salvinorin A are mediated by kappa receptors. Future studies may assist in the development and screening of salvinorin A analogs for potential pharmacotherapy.

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

“…Moreover, the KOPselective antagonist norBNI completely blocked the effects of salvinorin A but had no effect by itself. The research published by Baker et al (2009) extended these findings. In this study, conducted in rats, salvinorin A, and the metabolically stabilized salvinorin A analogs salvinorin B ethoxymethyl ether and salvinorin B methoxymethyl ether substituted completely for U69,593.…”

Acute and post-acute behavioral and psychological effects of salvinorin A in humans

“…Discrimination trials demonstrate SA to generalize to synthetic KOR agonists with both rodents (Baker et al 2009;Wilmore-Fordham et al 2007) and primates (Butelman et al 2004(Butelman et al , 2010. These generalization effects were blocked by general opioid antagonist quadazocine (Butelman et al 2004(Butelman et al , 2010 and KOR agonist norbinaltorphimine dihydrochloride ( Wilmore-Fordham et al 2007), were not blocked by 5-HT 2 antagonist ketanserin (Butelman et al 2010), and were partially blocked by KOR antagonist 5′-guanidinonaltrindole (effective in two of three monkeys; Butelman et al 2004).…”

Salvinorin A Analogs and Other Kappa-Opioid Receptor Compounds as Treatments for Cocaine Abuse

“…Sal A has been found to reliably, and fully substitute for U69,593 and U50,488 in drug discriminating studies in rodents following Sal A (1 mg/kg) (ip) (Baker, Panos, Killinger, Peet, Bell, Haliw et al, 2009) and also in primates (0.001–0.032 mg/kg) (subcutaneous, sc) (Butelman, Harris, & Kreek, 2004; Butelman, Rus, Prisinzano, & Kreek, 2010). Butelman et al (2004) showed a reversal of the discriminative stimulus effects of Sal A (0.001–0.032 mg/kg) (sc) by the KOPr antagonist quadazocine but not another KOPr antagonist 5’-guanidinonaltrindole (GNTI), This may be due to different binding site for Sal A compared to traditional KOPr agonists or differences in selectivity, onset of action or pharmacokinetic properties.…”