Effects of Salvinorin A, a κ-Opioid Hallucinogen, on a Neuroendocrine Biomarker Assay in Nonhuman Primates with High κ-Receptor Homology to Humans

Butelman, Eduardo R.; Mandau, Marek; Tidgewell, Kevin; Prisinzano, Thomas E.; Yuferov, Vadim; Kreek, Mary Jeanne

doi:10.1124/jpet.106.112417

Cited by 54 publications

(56 citation statements)

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“…Therefore, the present CSF detection data are consistent with brain -receptor occupancy by salvinorin A, at times when its robust behavioral and neuroendocrine effects are observed (Butelman et al, 2007). It has been pointed out that CSF concentrations of a particular ligand are not necessarily identical to brain extracellular concentrations under all conditions; therefore, this extrapolation should be interpreted with caution (Shen et al, 2004).…”

Section: Downloaded Fromsupporting

confidence: 68%

“…This study determined the effect of salvinorin A (0.032 mg/kg) after 30-min pretreatment with nalmefene (two doses, 0.01 or 0.1 mg/kg s.c., or vehicle). It is known that the smaller nalmefene dose (0.01 mg/kg) is sufficient to cause robust antagonism of -receptor-but not -receptor-mediated effects in this species (France and Gerak, 1994;Butelman et al, 2007). In contrast, nalmefene (0.1 mg/kg) is sufficient to cause antagonism of -receptor-mediated effects in this species.…”

Section: Studies With Sedation and Posture Observational Rating Scalesmentioning

confidence: 91%

“…The smaller nalmefene dose (0.01 mg/kg) was ineffective, whereas the larger dose (0.1 mg/kg) almost fully prevented the effects of salvinorin A. Prior studies in this species show that the smaller nalmefene dose is sufficient to block -receptor-mediated effects, whereas the larger dose can also block -receptor-mediated effects (France and Gerak, 1994;Butelman et al, 2007). Taken together, these data support the conclusion that salvinorin A's sedative and postural effects are mediated by -receptors.…”

Section: Discussionmentioning

confidence: 99%

“…One study in nonhuman primates focused on its operant discriminative effects in subjects trained to discriminate the synthetic -agonist U69,593 (Butelman et al, 2004). Studies on the overt behavioral effects of salvinorin A in nonhuman primate models may be especially valuable in view of reported differences between rodent and primate (including human) -opioid systems, at the neuroanatomical, neuropharmacological, and gene level (Young et al, 1986;Peckys and Landwehrmeyer, 1999;Liu-Chen, 2004;Butelman et al, 2007). Although there are descriptive reports on the behavioral and subjective effects of salvinorin A-containing products in humans, there is currently a lack of quantitative experimental data available (Siebert, 1994;Baggott et al, 2004;Gonzá lez et al, 2006).…”

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confidence: 99%

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

Butelman¹,

Prisinzano²,

Deng³

et al. 2008

J Pharmacol Exp Ther

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Salvinorin A is the main active component of the widely available hallucinogenic plant, Salvia divinorum. Salvinorin A is a selective high-efficacy -agonist in vitro, with some unique pharmacodynamic properties. Descriptive reports show that salvinorin A-containing products produce robust behavioral effects in humans. However, these effects have not been systematically characterized in human or nonhuman primates to date. Therefore, the present studies focused on the characterization of overt effects of salvinorin A, such as sedation (operationally defined as unresponsiveness to environmental stimuli) and postural relaxation, previously observed with centrally penetrating -agonists in nonhuman primates. Salvinorin A was active in these endpoints (dose range, 0.01-0

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Section: Downloaded Fromsupporting

confidence: 68%

Section: Studies With Sedation and Posture Observational Rating Scalesmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Butelman¹,

Prisinzano²,

Deng³

et al. 2008

J Pharmacol Exp Ther

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“…injection (John et al, 2006). Intravenous administration of Sal A increased prolactin levels in rhesus monkeys, but the duration was only 30 min, shorter than that of U69,593 (90 min) at the same dose (Butelman et al, 2007). A pharmacokinetic study in nonhuman primates showed that the elimination t 1/2 of Sal A in the serum was less than 1 h (Schmidt et al, 2005a).…”

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confidence: 99%

2-Methoxymethyl-Salvinorin B Is a Potent κ Opioid Receptor Agonist with Longer Lasting Action in Vivo Than Salvinorin A

Wang¹,

Chen²,

Xu³

et al. 2007

J Pharmacol Exp Ther

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Salvinorin (Sal) A is a naturally occurring, selective opioid receptor (KOPR) agonist with a short duration of action in vivo. Pharmacological properties of a C(2) derivative, 2-methoxymethyl (MOM)-Sal B, were characterized. MOM-Sal B bound to KOPR with high selectivity and displayed ϳ3-fold higher affinity than U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate] and Sal A. It acted as a full agonist at KOPR in guanosine 5Ј-O-(3-[ 35 S]thio)triphosphate binding and was ϳ5-and ϳ7-fold more potent than U50,488H and Sal A, respectively. In Chinese hamster ovary cells stably expressing KOPR, all three agonists internalized or down-regulated KOPR to similar extents, with MOM-Sal B being the most potent. In mice, MOM-Sal B (0.05-1 mg/kg s.c.) caused immediate and dose-dependent immobility lasting ϳ3 h, which was blocked by norbinaltorphimine. In contrast, ambulation in a Y-maze was increased when rats received MOM-Sal B (1-5 mg/kg s.c.). In addition, MOM-Sal B (0.5-5 mg/kg i.p.) produced antinociception (hot-plate test) and hypothermia in a dose-dependent manner in rats. MOM-Sal B was more potent than U50,488H in both tests and more efficacious than U50,488H in the hot-plate test. These latter two in vivo effects were blocked by norbinaltorphimine, indicating KOPR-mediated actions. Sal A at 10 mg/kg elicited neither antinociception nor hypothermia 30 min after administration to rats. In summary, MOM-Sal B is a potent and efficacious KOPR agonist with longer lasting in vivo effects than Sal A.Activation of the opioid receptor (KOPR), one of three major types of opioid receptors, produces many effects including analgesia, dysphoria, antipruritis, water diuresis, and hypothermia (Liu-Chen, 2004). Many selective nonpeptide KOPR agonists have been synthesized; most are arylacetamide compounds, including U50,488H, U69,593, ICI 204,448, and asimadoline. Nalfurafine is an exception, being an epoxymorphinan.Chewing or smoking the leaves of Salvia divinorum or drinking juice of crushed leaves causes hallucinations in humans (Siebert, 1994). Salvinorin (Sal) A (Fig. 1), a neoclerodane diterpene, was isolated and identified as the main active ingredient (Valdés, 1994). In a large scale screening of G protein-coupled receptors, transporters, and ion channels by radioligand binding assays, Roth et al. (2002) found that Sal A was a highly potent and selective agonist for the KOPR. Since then, several pharmacological studies on Sal A have been performed. Sal A binds to KOPR with a high affinity similar to U50,488H, a prototypic selective KOPR agonist. It does not show significant affinities to and ␦ opioid receptors or the nociceptin/orphanin FQ receptor . Sal A is reported to be more selective for KOPR than U50,488H or U69,593 (Beguin et al., 2008). Sal A acts as a very potent full agonist at KOPR in [35 S]GTP␥S binding, intracellular calcium mobilization, and potassium conductance assays (Chavkin et al., 2004;Wang et al., 2005). Sal A

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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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Effects of Salvinorin A, a κ-Opioid Hallucinogen, on a Neuroendocrine Biomarker Assay in Nonhuman Primates with High κ-Receptor Homology to Humans

Cited by 54 publications

References 32 publications

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

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

2-Methoxymethyl-Salvinorin B Is a Potent κ Opioid Receptor Agonist with Longer Lasting Action in Vivo Than Salvinorin A

Opioid Receptor Ligands

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