Salvinorin A, the active compound in the hallucinogenic plant Salvia divinorum, potently and selectively activates kappa opioid receptors while having no effect on the serotonin 5-HT(2A) receptor targeted by classical hallucinogens like LSD. This makes it the first known naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A produces perceptual distortions, the findings suggest that kappa opioid receptors play a key role in modulating human perception and that kappa opioid-selective antagonists could be developed as novel treatments for disorders involving perceptual distortions, such as schizophrenia, dementia, and bipolar disorders.
The kappa opioid receptor agonist salvinorin A, the active compound in Salvia divinorum, can either increase or decrease locomotor sensitization caused by the dopamine agonist quinpirole, depending on dose. Rats received biweekly injections of quinpirole plus salvinorin A (0.04, 0.4, or 2.0 mg/kg) or the synthetic kappa agonist U69593 (0.3 mg/kg) for ten sessions. The highest salvinorin A dose and U69593 both potentiated sensitization; the middle dose had no effect; the lowest dose attenuated it. Structural differences between salvinorin A and U69593 do not affect potentiation, and salvinorin A can bidirectionally modulate dopamine agonist sensitization.