The discriminative effects of the κ-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects

Abstract

Rationale The widely available hallucinogen salvinorin A is a unique example of a plant-derived compound selective for κ-opioid receptors and may produce effects distinct from those of other compounds with classic hallucinogenic or dissociative properties which are also abused in humans. Objectives The objective of this study is to characterize the salvinorin A discriminative cue in nonhuman primates with high κ-receptor genetic homology to humans. Methods Adult rhesus monkeys (n=3) were trained to discriminate salvinorin A (0.015 mg/kg, s.c.) from vehicle, in a food-reinforced operant discrimination assay. Parallel studies, using unconditioned behavioral endpoints (facial relaxation and ptosis) also evaluated the κ-opioid receptor mediation of salvinorin A in vivo function. Results Monkeys trained to discriminate salvinorin A generalized structurally diverse, centrally penetrating κ-agonists (bremazocine, U69,593, and U50,488). By contrast, μ- and δ-opioid agonists (fentanyl and SNC80, respectively) were not generalized, nor were the serotonergic 5HT2 hallucinogen psilocybin or the dissociative N-methyl-D-aspartic acid antagonist, ketamine. The discriminative effects of salvinorin A were blocked by the opioid antagonist quadazocine (0.32 mg/kg), but not by the 5HT2 antagonist ketanserin (0.1 mg/kg). Consistent with these findings, salvinorin and κ-agonists (e.g., U69,593) produce effects in the unconditioned endpoints (e.g., ptosis), whereas psilocybin was inactive. Conclusions These findings support the conclusion that the interoceptive/discriminative cue produced by salvinorin A is mediated by agonism at κ-receptors and is mechanistically distinct from that produced by a classic serotonergic hallucinogen.

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

“…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.…”

Acute and post-acute behavioral and psychological effects of salvinorin A in humans

“…Discrimination trials demonstrate SA to generalize to synthetic KOR agonists with both rodents (Baker et al 2009;Wilmore-Fordham et al 2007) and primates (Butelman et al 2004(Butelman et al , 2010. These generalization effects were blocked by general opioid antagonist quadazocine (Butelman et al 2004(Butelman et al , 2010 and KOR agonist norbinaltorphimine dihydrochloride ( Wilmore-Fordham et al 2007), were not blocked by 5-HT 2 antagonist ketanserin (Butelman et al 2010), and were partially blocked by KOR antagonist 5′-guanidinonaltrindole (effective in two of three monkeys; Butelman et al 2004).…”

“…These generalization effects were blocked by general opioid antagonist quadazocine (Butelman et al 2004(Butelman et al , 2010 and KOR agonist norbinaltorphimine dihydrochloride ( Wilmore-Fordham et al 2007), were not blocked by 5-HT 2 antagonist ketanserin (Butelman et al 2010), and were partially blocked by KOR antagonist 5′-guanidinonaltrindole (effective in two of three monkeys; Butelman et al 2004). Further, discrimination trials demonstrate that SA does not generalize to 5-HT 2 agonists 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane ( Li et al 2008), d-lysergic acid diethylamide (LSD; Killinger et al 2010), or psilocybin (Butelman et al 2010); CB1 agonist delta-9-tetrahydrocannabinol (Walentiny et al 2010); delta opioid receptor agonist SNC80 (Butelman et al 2010); mu opioid receptor agonist fentanyl (Butelman et al 2010); or NMDA antagonist ketamine (Butelman et al 2010;Killinger et al 2010).…”

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

“…Neither U69,593 nor salvinorin A was shown to substitute for 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane. Butelman et al (2010) further showed that structurally diverse KOP agonists (bremazocine, U69,593, U50,488), but not psilocybin, a 5-HT 2A receptor agonist that is hallucinogenic in humans, substituted for salvinorin A in rhesus monkeys trained to discriminate salvinorin A from saline. Nemeth et al (2010) compared the effects of ketamine and salvinorin A in the five-choice serial reaction time task (5CSRTT) in rats.…”