Salvinorin A inhibits colonic transit and neurogenic ion transport in mice by activating κ-opioid and cannabinoid receptors

Abstract  The major active ingredient of the plant Salvia divinorum , salvinorin A (SA) has been used to treat gastrointestinal (GI) symptoms. As the action of SA on the regulation of colonic function is unknown, our aim was to examine the effects of SA on mouse colonic motility and secretion in vitro and in vivo . The effects of SA on GI motility were studied using isolated preparations of colon, which were compared with preparations from stomach and ileum. Colonic epithelial ion transport was evaluated using Ussing chambers. Additionally, we studied GI motility in vivo by measuring colonic propulsion, gastric emptying, and upper GI transit. Salvinorin A inhibited contractions of the mouse colon, stomach, and ileum in vitro , prolonged colonic propulsion and slowed upper GI transit in vivo . Salvinorin A had no effect on gastric emptying in vivo . Salvinorin A reduced veratridine-, but not forskolin-induced epithelial ion transport. The effects of SA on colonic motility in vitro were mediated by κ-opioid receptors (KORs) and cannabinoid (CB) receptors, as they were inhibited by the antagonists nor-binaltorphimine (KOR), AM 251 (CB₁ receptor) and AM 630 (CB₂ receptor). However, in the colon in vivo , the effects were largely mediated by KORs. The effects of SA on veratridine-mediated epithelial ion transport were inhibited by nor-binaltorphimine and AM 630. Salvinorin A slows colonic motility in vitro and in vivo and influences neurogenic ion transport. Due to its specific regional action, SA or its derivatives may be useful drugs in the treatment of lower GI disorders associated with increased GI transit and diarrhoea.     

In vitro studies on metabolism of salvinorin A

Microbial transformation of natural products is a well established model for mammalian metabolism. Salvinorin A, a diterpenoid isolated from the hallucinogenic mint Salvia divinorum Epling & Játiva-M (Lamiaceae), is a potent non-nitrogenous κ-opioid receptor agonist. The metabolism of salvinorin A has still not yet been well established. Thirty fungal species were screened for the ability to metabolize salvinorin A. We observed that salvinorin A undergoes fast hydrolysis of the acetate group at carbon atom C2, resulting in formation of the pharmacologically inactive product, salvinorin B. Ex vivo experiments were also performed using organelle fractions isolated from rat liver and brain. Crude tissue homogenate and individual organelles show that the primary route of salvinorin A metabolism is hydrolysis to salvinorin B. No metabolic transformation of salvinorin B was observed in these studies.     

The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin A inhibit enteric cholinergic transmission in the guinea-pig ileum.

Salvia divinorum is a widespread hallucinogenic herb traditionally employed for divination, as well as a medicament for several disorders including disturbances of gastrointestinal motility. In the present study we evaluated the effect of a standardized extract from the leaves of S. divinorum (SDE) on enteric cholinergic transmission in the guinea-pig ileum. SDE reduced electrically evoked contractions without modifying the contractions elicited by exogenous acetylcholine, thus suggesting a prejunctional site of action. The inhibitory effect of SDE on twitch response was abolished by the opioid receptor antagonist naloxone and by the kappa-opioid antagonist nor-binaltorphimine, but not by naltrindole (a delta-opioid receptor antagonist), CTOP (a mu-opioid receptor antagonist), thioperamide (a H(3) receptor antagonist), yohimbine (an alpha(2)-receptor antagonist), methysergide (a 5-hydroxytryptamine receptor antagonist), N(G)-nitro-L-arginine methyl ester (an inhibitor of NO synthase) or apamin (a blocker of Ca(2+)-activated K(+) channels). Salvinorin A, the main active ingredient of S. divinorum, inhibited in a nor-binaltorphimine- and naloxone-sensitive manner electrically induced contractions. It is concluded that SDE depressed enteric cholinergic transmission likely through activation of kappa-opioid receptors and this may provide the pharmacological basis underlying its traditional antidiarrhoeal use. Salvinorin A might be the chemical ingredient responsible for this activity.     

Salvia divinorum: from Mazatec medicinal and hallucinogenic plant to emerging recreational drug

Salvia divinorum is a sage endemic to a small region of Mexico and has been traditionally used by the Mazatec Indians for divination and spiritual healing. Recently, it has gained increased popularity as a recreational drug, used by adolescents and young adults as an alternative to marijuana and LSD. Salvinorin A, the major active ingredient of the plant, is considered to be the most potent known hallucinogen of natural origin. This review surveys the current state of knowledge on the neurochemical, pharmacokinetic, and pharmacological properties of salvinorin A, the trends and motivation behind S. divinorum use, and the health problems among users of the plant's products. S. divinorum induces intense, but short‐lived, psychedelic‐like changes in mood and perception, with concomitant hallucinations and disorientation. Many websites have misinterpreted the limited existing research‐based information on the side effects of salvia as evidence for its safety. However, data accumulated over the last few years indicate that potential health risks are associated with the use of S. divinorum, especially by teenagers, users of other substances of abuse, and individuals with underlying psychotic disturbances. Taken together, the data presented in this review point to the need for further basic and clinical studies to create a basis for the development of well‐addressed prevention and treatment strategies. Copyright © 2013 John Wiley & Sons, Ltd.     

Opiate Agonist and Antagonist Receptors

Abstract

Salvia divinorum is a vision-inducing mint used by the Mazatec people of Oaxaca, Mexico. It is grown in California and other parts of the United States where it is employed as a legal hallucinogen. Traditional opinion has been that the plant has mild psychotropic activity, at best. However, when ingested in the correct manner, it is quite powerful. The fresh leaves are chewed as a quid and kept in the mouth. They may also be eaten raw or prepared as an aqueous infusion. When dried, they are smoked in the manner of marijuana. The neoclerodane diterpcne, salvinorin A (also known as divinorin A), has been demonstrated in animals and humans to be its major active ingredient. Essentially inactive if taken orally, the compound is effective in doses of 200 to 500 mcg when smoked in a manner similar to cocaine free base. This makes salvinorin A the first documented diterpene hallucinogen and the most potent naturally occurring hallucinogen thus far isolated. This is somewhat remarkable, since the compound is not an alkaloid. This article reviews the use of S. divinorum and its chemistry. In addition, it discusses the effects of the plant and salvinorin A in animals and humans, as well as their potential to become drugs of abuse.     

Pharmacology and anti-addiction effects of the novel κ opioid receptor agonist Mesyl Sal B,a potent and long-acting analogue of salvinorin A

BACKGROUND AND PURPOSE

Acute activation of κ opioid (KOP) receptors results in anticocaine-like effects, but adverse effects, such as dysphoria, aversion, sedation and depression, limit their clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi-synthetic analogues have been shown to have potent KOP receptor agonist activity and may induce a unique response with similar anticocaine addiction effects as the classic KOP receptor agonists, but with a different side effect profile.

EXPERIMENTAL APPROACH

We evaluated the duration of effects of Mesyl Sal B in vivo utilizing antinociception assays and screened for cocaine-prime induced cocaine-seeking behaviour in self-administering rats to predict anti-addiction effects. Cellular transporter uptake assays and in vitro voltammetry were used to assess modulation of dopamine transporter (DAT) function and to investigate transporter trafficking and kinase signalling pathways modulated by KOP receptor agonists.

KEY RESULTS

Mesyl Sal B had a longer duration of action than SalA, had anti-addiction properties and increased DAT function in vitro in a KOP receptor-dependent and Pertussis toxin-sensitive manner. These effects on DAT function required ERK1/2 activation. We identified differences between Mesyl Sal B and SalA, with Mesyl Sal B increasing the V_max of dopamine uptake without altering cell-surface expression of DAT.

CONCLUSIONS AND IMPLICATIONS

SalA analogues, such as Mesyl Sal B, have potential for development as anticocaine agents. Further tests are warranted to elucidate the mechanisms by which the novel salvinorin-based neoclerodane diterpene KOP receptor ligands produce both anti-addiction and adverse side effects.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

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

Salvinorin A, a potent hallucinogen isolated from the leaves of Salvia divinorum, has gained popularity among adolescents in the USA. No detailed study of the pharmacokinetics has been conducted in vivo. The present study investigates the in vivo pharmacokinetics of salvinorin A (0.032 mg/kg, i.v. bolus) in rhesus monkeys (n=4, 2 male, 2 female). The elimination t(1/2) was rapid (56.6+/-24.8 min) for all subjects. Pharmacokinetic differences (distribution t(1/2), elimination t(1/2), and AUC) were observed between males and females, suggesting potential sex differences in its pharmacologic effects. Salvinorin B, the presumed major metabolite, is observed to accumulate ex vivo; however, in this study it never reached the limit of detection.     

Adolescent salvia substance abuse

BACKGROUND: Salvia divinorum is a non-water-soluble hallucinogen that is becoming increasingly popular among adolescents. Salvia is a highly selective full agonist of primate and cloned human cerebral kappa-opioid receptors, although its psychotomimetic effects are similar to serotonergic agonists and NMDA glutamate antagonists. Salvia has been associated with depersonalization, laughter, feelings of levitation and self-consciousness. These effects resolve within 30 minutes following use. Salvia has been banned in many countries, although it remains legal and easily assessable over the internet in the United States. CASE DESCRIPTION: A 15-year-old man with a history of salvia and marijuana use presented to psychiatric emergency services with acute onset of mental status changes characterized by paranoia, déjà vu, blunted affect, thought blocking and slow speech of 3 days' duration. CONCLUSION: There is limited literature discussing the clinical effects of salvia use. Based on this case presentation, salvia use may be associated with many undocumented long-term effects such as déjà vu. The ease of use and increasing popularity of salvia requires further investigation into the clinical effects of salvia use.     

The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin A reduce inflammation-induced hypermotility in mice.

The hallucinogenic plant Salvia divinorum has been used for medical treatments of gastrointestinal disorders. Here, we evaluated the effect of a standardized extract from the leaves of Salvia divinorum (SDE) and of its active ingredient salvinorin A on motility in vivo, both in physiological states and during croton oil-induced intestinal inflammation. SDE (1-100 mg kg(-1)) significantly inhibited motility only in inflamed, but not in control, mice. In control mice, salvinorin A (0.01-10 mg kg(-1)) significantly inhibited motility only at the highest doses tested (3 and 10 mg kg(-1)) and this effect was not counteracted by naloxone or by the kappa-opioid receptor (KOR) antagonist nor-binaltorphimine. Inflammation significantly increased the potency of salvinorin A (but not of the KOR agonist U-50488) in reducing motility. The inhibitory effects of both salvinorin A and U-50488 in inflamed mice were counteracted by naloxone or by nor-binaltorphimine. We conclude that salvinorin A may reduce motility through activation of different targets. In physiological states, salvinorin A, at high doses, inhibited motility through a non-KOR mediated mechanism. Gut inflammation increased the potency of salvinorin A; this effect was mediated by KOR, but it was not shared by U-50488, thus suggesting that salvinorin A may have target(s) other than KOR in the inflamed gut.