Unconditioned Behavioral Effects of the Powerful κ-Opioid Hallucinogen Salvinorin A in Nonhuman Primates: Fast Onset and Entry into Cerebrospinal Fluid

Butelman, Eduardo R.; Prisinzano, Thomas E.; Deng, Haiteng; Rus, Szymon; Kreek, Mary Jeanne

doi:10.1124/jpet.108.145342

Cited by 63 publications

(90 citation statements)

References 35 publications

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“…Unconditioned Behavioral Effects of Salvinorin A: Ptosis and Facial Relaxation. These behavioral endpoints were chosen based on prior studies in which they were used to characterize salvinorin A and, in particular, its rapid-onset (Butelman et al, 2009). Effects of salvinorin A in these endpoints can also be blocked by the opioid antagonist nalmefene, at doses consistent with mediation by -receptors (Butelman et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

“…Thus, scores for each behavior in a time window ranged from 0 to 60 s. Very brief events (Ͻ1 s in duration) were not scored to avoid baseline behaviors such as blinking. Salvinorin A and synthetic -agonists cause rapid-onset, robust, and dose-dependent ptosis and facial relaxation, at doses that also result in unresponsiveness to environmental stimuli, an operational measure of sedation (Butelman et al, 2009; see also relevant human data in Ur et al, 1997). An analysis of humans under the influence of S. divinorum in a naturalistic setting revealed qualitatively similar effects, supporting translational relevance for these dependent variables (Lange et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

“…These behavioral endpoints were chosen based on prior studies in which they were used to characterize salvinorin A and, in particular, its rapid-onset (Butelman et al, 2009). Effects of salvinorin A in these endpoints can also be blocked by the opioid antagonist nalmefene, at doses consistent with mediation by -receptors (Butelman et al, 2009). It is also known that a peripherally selective -agonist exhibits low potency and low effectiveness in these behavioral endpoints, compared with its profile in a neuroendocrine endpoint thought to be mediated by -receptors outside of the BBB (Butelman et al, 1999(Butelman et al, , 2010.…”

Section: Methodsmentioning

confidence: 99%

“…As described previously (Butelman et al, 2009), the cumulative duration of two specific behaviors was separately quantified in videotaped chaired subjects in 1-min time windows: ptosis (eye closure; partial or complete) and facial relaxation. Thus, scores for each behavior in a time window ranged from 0 to 60 s. Very brief events (Ͻ1 s in duration) were not scored to avoid baseline behaviors such as blinking.…”

Section: Methodsmentioning

confidence: 99%

“…Variability in subject sensitivity and potential vulnerability to untoward effects of salvinorin A-containing products has also been reported (Singh, 2007;Przekop and Lee, 2009;Siebert, 2010;Johnson et al, 2011). Studies in nonhuman primates have evaluated the detailed time course of unconditioned salvinorin A effects and characterized a set that parallels effects seen in humans (i.e., rapid onset and entry into the CNS) (Butelman et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Behavioral Effects and Central Nervous System Levels of the Broadly Available κ-Agonist Hallucinogen Salvinorin A Are Affected by P-Glycoprotein Modulation In Vivo

Butelman¹,

Caspers²,

Lovell³

et al. 2012

J Pharmacol Exp Ther

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Active blood-brain barrier mechanisms, such as the major efflux transporter P-glycoprotein (mdr1), modulate the in vivo/ central nervous system (CNS) effects of many pharmacological agents, whether they are used for nonmedical reasons or in pharmacotherapy. The powerful, widely available hallucinogen salvinorin A (from the plant Salvia divinorum) is a high-efficacy, selective -opioid agonist and displays fast-onset behavioral effects (e.g., within 1 min of administration) and relatively short duration of action. In vitro studies suggest that salvinorin A may be a P-glycoprotein substrate; thus, the functional status of P-glycoprotein may influence the behavioral effects of salvinorin A or its residence in CNS after parenteral administration. We therefore studied whether a competing P-glycoprotein substrate (the clinically available agent loperamide; 0.032-0.32 mg/kg) or a selective P-glycoprotein blocker, tariquidar (0.32-3.2 mg/kg) could enhance unconditioned behavioral effects (ptosis and facial relaxation, known to be caused by -agonists in nonhuman primates) of salvinorin A, as well as its entry and residence in the CNS, as measured by cerebrospinal fluid sampling. Pretreatment with either loperamide or tariquidar dosedependently enhanced salvinorin A-induced ptosis, but not facial relaxation. In a control study, loperamide and tariquidar were inactive when given as a pretreatment to (U69,593), a -agonist known to be a very poor P-glycoprotein substrate. Furthermore, pretreatment with tariquidar (3.2 mg/kg) also enhanced peak levels of salvinorin A in cerebrospinal fluid after intravenous administration. These are the first studies in vivo showing the sensitivity of salvinorin A effects to modulation by the P-glycoprotein transporter, a major functional component of the blood-brain barrier.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Behavioral Effects and Central Nervous System Levels of the Broadly Available κ-Agonist Hallucinogen Salvinorin A Are Affected by P-Glycoprotein Modulation In Vivo

Butelman¹,

Caspers²,

Lovell³

et al. 2012

J Pharmacol Exp Ther

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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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