The plant-derived hallucinogen, salvinorin A, produces κ-opioid agonist-like discriminative effects in rhesus monkeys
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Salvinorin A is the active component of the hallucinogenic plant Salvia divinorum. The potential mode of action of this hallucinogen was unknown until recently. A recent in vitro study detected high affinity and efficacy of salvinorin A at κ-opioid receptors. It was postulated that salvinorin A would produce discriminative stimulus effects similar to those of a high efficacy κ-agonist (U69,593) in rhesus monkeys.
Monkeys were previously trained to discriminate U69,593 (0.0056 or 0.013 mg/kg; SC) from vehicle in a food-reinforced FR20 (fixed ratio 20) operant conditioning procedure (n=3). The ability of salvinorin A to cause generalization (≥90% U69,593-appropriate responding) was examined in time course and cumulative dose-effect curve studies.
All subjects dose-dependently emitted full U69,593-appropriate responding after salvinorin A (0.001–0.032 mg/kg, SC). Salvinorin A-induced generalization started 5–15 min after injection, and dissipated by 120 min. The opioid antagonist quadazocine (0.32 mg/kg) fully blocked the effects of salvinorin A. The κ-selective antagonist GNTI (1 mg/kg; 24 h pretreatment) did not cause significant antagonism of the effects of salvinorin A (GNTI, under these conditions, was only effective as an antagonist in two of three monkeys). The NMDA antagonist ketamine (0.1–3.2 mg/kg) was not generalized by any subject, indicating that not all compounds that produce hallucinogenic or psychotomimetic effects in humans are generalized by subjects trained to discriminate U69,593.
The naturally occurring hallucinogen salvinorin A produces discriminative stimulus effects similar to those of a high efficacy κ-agonist in non-human primates.
Keywordsκ-Opioid Salvinorin A Drug discrimination Hallucinogen
The present studies were supported by National Institutes of Health/NIDA grants DA11113 (E.R.B.), DA05130 and DA00049 (M.J.K.).
- Butelman ER, Ball JW, Kreek MJ (2003) Peripheral selectivity and apparent efficacy of dynorphins: comparison to non-peptidic kappa-opioid agonists in rhesus monkeys. Psychoneuroendocrinology (in press)Google Scholar
- Drug Enforcement Administration (2002) List of drugs and chemicals of concern. Internet website: www deadiversion usdoj gov/drugs_concern/salvia_d/summary.htmGoogle Scholar
- France CP, Snyder AM, Woods JH (1989) Analgesic effects of phencyclidine-like drugs in rhesus monkeys. J Pharmacol Exp Ther 250:197–201Google Scholar
- Giroud C, Felber F, Augsburger M, Horisberger B, Rivier L, Mangin P (2000) Salvia divinorum: an hallucinogenic mint which might become a new recreational drug in Switzerland. Forens Sci Int 112:143–150Google Scholar
- Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214PubMedGoogle Scholar
- Observateur francais des drogues et des toxicomanies (2002) Premier identification du principle actif de la salvia divinorum dans SINTES. Internet website: www.drogues.gouv fr/fr/professionels/info_rapides_trend/info19_07_2002.htmlGoogle Scholar
- Ortega A, Blount JF, Marchand P (1982) Salvinorin, a new trans-neoclerodane diterpene from Salvia divinorum (Labiatae). J Chem Soc Perkins Transact 1:2505–2508Google Scholar
- Pfeiffer A, Brantl V, Herz A, Emrich HM (1986) Psychotomimesis mediated by kappa opiate receptors. Science 233:774–776Google Scholar
- Remmers AE, Clark MJ, Mansour A, Akil H, Woods JH, Medzihradsky F (1999) Opioid efficacy in a C6 glioma cell line stably expressing the human kappa opioid receptor. J Pharmacol Exp Ther 288:827–833Google Scholar
- Valdes LJ (1994) Salvia divinorum and the unique diterpene hallucinogen, salvinorin (divinorin) A. J Psychoact Drugs 26:277–283Google Scholar