Pharmacokinetics of the plant-derived κ-opioid hallucinogen salvinorin A in nonhuman primates

Schmidt, Matthew; Schmidt, Mark S.; Butelman, Eduardo R.; Harding, Wayne W.; Tidgewell, Kevin; Murry, Daryl J.; Kreek, Mary Jeanne; Prisinzano, Thomas E.

doi:10.1002/syn.20191

Cited by 79 publications

(97 citation statements)

References 18 publications

(22 reference statements)

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“…than the s.c. route in males. Reasons for this are unclear but may be related to pharmacokinetic factors, possibly limiting bioavailability by the s.c. route (Schmidt et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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

Butelman¹,

Mandau²,

Tidgewell³

et al. 2006

J Pharmacol Exp Ther

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This study focused on the in vivo effects of the -opioid hallucinogen salvinorin A, derived from the plant Salvia divinorum. The effects of salvinorin A (0.0032-0.056 mg/kg i.v.) were studied in a neuroendocrine biomarker assay of the anterior pituitary hormone prolactin in gonadally intact, adult male and female rhesus monkeys (n ϭ 4 each). Salvinorin A produced dose-and time-dependent neuroendocrine effects, similar to the synthetic high-efficacy -agonist U69,593but of shorter duration than the latter. Salvinorin A was approximately equipotent to U69,593 in this endpoint (salvinorin A ED 50 , 0.015 mg/kg; U69,593 ED 50 , 0.0098 mg/kg). The effects of i.v. salvinorin A were not prevented by a small dose of the opioid antagonist nalmefene (0.01 mg/kg s.c.) but were prevented by a larger dose of nalmefene (0.1 mg/kg); the latter nalmefene dose is sufficient to produce -antagonist effects in this species. In contrast, the 5HT2 receptor antagonist ketanserin (0.1 mg/kg i.m.) did not prevent the effects of salvinorin A. As expected, the neuroendocrine effects of salvinorin A (0.0032 mg/kg i.v.) were more robust in female than in male subjects. Related studies focused on full-length cloning of the coding region of the rhesus monkey -opioid receptor (OPRK1) gene and revealed a high homology of the nonhuman primate OPRK1 gene compared with the human OPRK1 gene, including particular C-terminal residues thought to be involved in receptor desensitization and internalization. The present studies indicate that the hallucinogen salvinorin A acts as a high-efficacy -agonist in nonhuman primates in a translationally viable neuroendocrine biomarker assay.

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“…than the s.c. route in males. Reasons for this are unclear but may be related to pharmacokinetic factors, possibly limiting bioavailability by the s.c. route (Schmidt et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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

Butelman¹,

Mandau²,

Tidgewell³

et al. 2006

J Pharmacol Exp Ther

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“…in male and female rhesus monkeys (Schmidt et al, 2005a). Although the overall elimination t 1/2 was 56.6 Ϯ 24.8 min, distinct gender differences were observed: in male monkeys, there was a rapid t 1/2 for distribution, elimination t 1/2 was 37.9 Ϯ 5.6 min, and the area under the dose-response curve was 572 Ϯ 133 ng ⅐ min Ϫ1 ⅐ ml Ϫ1 , whereas in female monkeys, t 1/2 for distribution was slower (0.95 Ϯ 0.2 min), the t 1/2 for elimination was 80.0 Ϯ 13.1 min, and the area under the dose-response curve was 1087 Ϯ 46 ng ⅐ min Ϫ1 ⅐ ml Ϫ1 .…”

Section: B Pharmacokinetic Properties Of Salvinorin Amentioning

confidence: 99%

“…It was also demonstrated ex vivo that salvinorin B is the major metabolite of salvinorin A in nonhuman primates . The concentration of salvinorin B was below the limit of quantitation in rhesus monkey plasma, however, suggesting that this metabolite is either cleared rapidly or accumulates in organs or tissues (Schmidt et al, 2005a). That salvinorin A is rapidly metabolized is supported by the finding that only approximately 0.8% of an administrated dose of salvinorin A (0.5 mg) was extracted from urine in human volunteers (Pichini et al, 2005).…”

Section: A Metabolism Of Salvinorin Amentioning

confidence: 99%

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

2011

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“…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).…”

mentioning

confidence: 94%

“…However, Sal B was not detected in the blood after i.v. injection of Sal A in rhesus monkeys (Schmidt et al, 2005a). Sal B may be accumulated in the extravascular compartment or be excreted via other routes.…”

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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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Pharmacokinetics of the plant-derived κ-opioid hallucinogen salvinorin A in nonhuman primates

Cited by 79 publications

References 18 publications

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

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

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

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

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