Unconditioned behavioral effects of the powerful kappa-opioid hallucinogen salvinorin A in nonhuman primates: fast onset and entry into cerebrospinal fluid.

Salvinorin A is the main active component of the widely available hallucinogenic plant, Salvia divinorum. Salvinorin A is a selective high-efficacy kappa-agonist in vitro, with some unique pharmacodynamic properties. Descriptive reports show that salvinorin A-containing products produce robust behavioral effects in humans.

Peripheral selectivity and apparent efficacy of dynorphins: comparison to non-peptidic kappa-opioid agonists in rhesus monkeys.

The potency and effectiveness of dynorphin A(1-17), E-2078 (a synthetic dynorphin A(1-8) analog) and non-peptidic kappa-opioid agonists were studied in rhesus monkeys in two assays: 1) a drug discrimination assay with the centrally-penetrating kappa-agonist U69,593 as the training stimulus (n=3) and 2) a prolactin release assay; a neuroendocrine effect thought to be mediated by kappa-receptors located in hypothalamic nuclei outside the blood-brain barrier. The non-peptidic kappa-agonists, U69,593 and bremazocine (0.00032-0.

Comparison of the discriminative and neuroendocrine effects of centrally penetrating kappa-opioid agonists in rhesus monkeys.

Rationale: The discriminative effects of kappa-agonists may be mediated centrally, whereas their effects in a neuroendocrine biomarker assay (prolactin release) may be mediated by kappa-receptors in hypothalamic areas outside the blood-brain barrier. Prolactin may thus be a useful biomarker, due to its potential to provide quantitative pharmacodynamic data for kappa-opioid ligands in vivo. The potency of centrally penetrating kappa-agonists could be similar in these two assays, due to their ability to occupy kappa-receptor pools inside and outside the blood-brain barrier, following SC administration.

kappa-Opioid receptor agonist-induced prolactin release in primates is blocked by dopamine D(2)-like receptor agonists.

Kappa-opioid receptor agonists may have pharmacotherapeutic potential in the management of psychostimulant abuse, due to their ability to modulate dopamine receptor systems involved in drug reinforcement. kappa-Opioid receptor agonists also modulate dopamine receptor function in the hypothalamic tuberoinfundibular system, which has inhibitory control over an anterior pituitary hormone, prolactin. Prolactin levels may thus be a "biomarker" for the ability of kappa-opioid receptor agonists (e.