Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist

Abstract

Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum extracts and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited 3 H-bremazocine binding to cloned opioid receptors. Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent opioid agonist at cloned opioid receptors expressed in human embryonic kidney-293 cells and at native opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT 2A serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for opioid receptors, opioid-selective antagonists may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Additionally, these results suggest that opioid receptors play a prominent role in the modulation of human perception.

Evidence for the Preferential Involvement of 5-HT2A Serotonin Receptors in Stress- and Drug-Induced Dopamine Release in the Rat Medial Prefrontal Cortex

“…Cell lines stably transfected with recombinant cDNA encoding receptors or cell lines that express endogenous receptors were used for the comprehensive screening using the resources of the National Institute of Mental Health's Psychoactive Drug Screening Program (PDSP) as previously detailed . The recombinant receptors included (1) human adrenergic receptors, a1A, a1B, a2A, a2B, a2C, and rat adrenergic receptors, b1 and b2; (2) rat cannabanoid CB1 receptor; (3) dopaminergic receptors, hD1, rD2, rD3, rD4, and hD5; (4) human histamine receptors, H1, H2, and H4; (5) rat imidazoline receptor; (6) human muscarinic acetylcholine receptors, M1, M2, M3, M4, and M5; (7) human nicotinic acetylcholine receptors, a2/b2, a2/b4, a3/b2, a3/b4, a4/b2, and a4/b4; (8) human opiate receptors, m, d, and k; (9) human peptide receptors, V1, V2, V3, and OT; (10) serotonergic receptors, h5-HT1A, r5-HT1B, h5-HT1E, r5-HT2A, h5-HT2B, r5-HT2C, h5-HT3, h5-HT5A, h5-HT6, and h5-HT7; (11) human transporters of serotonin, norepinephrine, and dopamine as previously described (Roth et al, 1998;Rothman et al, 2000;Roth et al, 2001;Roth et al, 2002;Shapiro et al, 2002); and (12) rat metabotropic glutamate receptors, mGluR1a, mGluR2, mGluR4, mGluR5a, mGluR6, and mGluR8 as previously described (Gomeza et al, 1996;Wroblewska et al, 1997;Kozikowski et al, 1998;Shi et al, 2003). The endogenous receptors included (1) GABA receptors, GABA A , GABA B , and GABA BZP from rat forebrain; (2) histamine receptor H1 from rat forebrain; (3) rat nicotinic acetylcholine receptor, a4/b2; (4) ionotropic NMDA glutamate receptor from rat forebrain; and (5) voltage-sensitive Ca 2 þ channel from rat heart.…”

Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats

“…SalB is a metabolite of the KOR selective agonist salvinorin A (SalA) that has minimal or no affinity to KOR and numerous other receptors, as assessed in receptor binding assays (Roth et al, 2002;Ansonoff et al, 2006). SalB also has minimal or no observed behavioral effects in mice under conditions in which SalA is highly effective (eg, increases in brain stimulation threshold) (Vardy et al, 2015).…”

Perspectives on Zebrafish Models of Hallucinogenic Drugs and Related Psychotropic Compounds

“…Opioidergic agent salvinorin A (acting as a kappa opioid receptor agonist) also possesses strong dissociative (and some psychedelic) hallucinogenic properties in humans, 37,38 and affects behavior in animals. 39−41 Some hallucinogenic agents, such as psychedelic drug ibogaine, have mixed pharmacological profiles, combining antagonism of NMDA receptors with serotonergic and opioidergic agonism (Table 1).…”