The hallucinogen derived from Salvia divinorum, salvinorin A, has κ-opioid agonist discriminative stimulus effects in rats

Willmore-Fordham, Catherine B.; Krall, Daniel M.; McCurdy, Christopher R.; Kinder, David H.

doi:10.1016/j.neuropharm.2007.06.008

Cited by 41 publications

(46 citation statements)

References 32 publications

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“…Previous studies have demonstrated that salvinorin A substitutes in monkeys (Butelman et al 2004) or rats (Willmore-Fordham et al 2007) trained to discriminate the kappa agonist, U69,593, and that these effects are attenuated by KOP antagonists. The present results are consistent with these reports and extend these findings to a lower dose of the U69,593 and to another kappa agonist, U50,488.…”

Section: Discussionmentioning

confidence: 99%

“…The present results are consistent with these reports and extend these findings to a lower dose of the U69,593 and to another kappa agonist, U50,488. Willmore-Fordham et al (2007) trained rats to discriminate a considerably higher dose of U69,593 (0.56 mg/kg, i.p., 10 min) than the one employed in the current study (0.13 mg/kg, s.c., 30 min). In addition, all three doses of salvinorin A that they tested (1.0, 1.9, and 3.0 mg/kg) produced full substitution for U69,593 without significantly reducing response rates.…”

Section: Discussionmentioning

confidence: 99%

“…Due to limited solubility of these compounds, they were initially dissolved in DMSO and then diluted with sterile water to 75% DMSO. This vehicle has been used in a previous study (Willmore-Fordham et al 2007) and was well-tolerated by the animals in the current study. There were no obvious signs of tissue necrosis following repeated injections with this vehicle.…”

Section: Drugsmentioning

confidence: 99%

“…Drug discrimination procedures are a well-established animal model for classifying novel compounds with putative psychoactive actions because they allow for a comparison between novel substances and known psychoactive drugs (Schuster and Johanson 1988;Balster 1991). Salvinorin A has not yet been evaluated extensively in drug discrimination procedures, although a few studies have tested salvinorin A in rhesus monkeys (Butelman et al 2004) or rats (Willmore-Fordham et al 2007) trained to discriminate the kappa agonist U69,593 or monkeys trained to discriminate the serotonergic hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM; Li et al 2008). Butelman et al (2004) demonstrated stimulus generalization to salvinorin A in three rhesus monkeys trained to discriminate the kappa agonist, U69,593.…”

mentioning

confidence: 99%

“…In a more recent study, Willmore-Fordham et al (2007) trained ten male Sprague-Dawley rats to discriminate 0.56 mg/kg U69,593 (i.p., 10 min) and tested a range of salvinorin A doses (1.0-3.0 mg/kg) for substitution. At all doses tested, salvinorin A exhibited full substitution for U69,593 and these effects were blocked by i.c.v.…”

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confidence: 99%

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

et al. 2009

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Drugsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2009

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Opioid Receptor Ligands

McCurdy

Prisinzano

2010

Burger's Medicinal Chemistry and Drug Discovery

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Opioid agonists, exemplified by morphine, have been the most prescribed class of drugs for the management of moderate to severe pain for many years. These drugs have significant liabilities of addiction and constipation over long‐term use and acute overdoses can result in respiratory depression. For over thousands of years, opium and opium‐derived drugs have nonetheless been utilized for their therapeutic and recreational benefits. Due to their liabilities, medicinal chemists and clinicians have worked for years to discover novel agents or treatment courses that would be devoid of these side effects. Still to this day, there are no agents that meet these criteria. Therefore, efforts continue vigorously in the quest for drugs with potent analgesic effects without abuse or side‐effect potential. Many chemical classes have been sought after in this quest and the range from peptides to synthetic compounds to natural products. Morphine offered a template that was rigid and able to provide an enormous amount of structure–function relationships that many of the market analgesics are based on. To complicate matters, the endogenous opioid system is comprised of four distinct receptor subtypes. These receptors are all members of the G‐protein superfamily and are designated as mu (μ, MOP), delta (δ, DOP), kappa (κ, KOP), and nociception (ORL1, NOP). It has been realized over the years that a combination of activities at these receptors may result in agents that could be devoid of liabilities. Intensive efforts have been directed at improved probes for each receptor subtype and combinations of agonists and antagonists for combinations of these receptors. This review will discuss the structure–activity relationships, as they are currently understood, with regard to each of the major classes of compounds that interact with these protein targets.

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