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BEHAVIORAL PHARMACOLOGY

Antinociceptive and Hypothermic Effects of Salvinorin A Are Abolished in a Novel Strain of -Opioid Receptor-1 Knockout Mice

Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School (UMDNJ-RWJMS), Piscataway, New Jersey (M.A.A., J.Z., T.C., J.E.P.); Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio (J.S., J.Z., F.Y., B.L.R.), Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (R.B.R., H.X.); and Malibu, California (D.J.S.)

Salvia divinorum is a natural occurring hallucinogen that is traditionally used by the Mazatec Indians of central Mexico. The diterpene salvinorin A was identified as an active component of S. divinorum over 20 years ago, but only recently has biochemical screening indicated that a molecular target of salvinorin A in vitro is the -opioid receptor. We have examined whether salvinorin A, the C2-substituted derivative salvinorinyl-2-propionate, and salvinorin B can act as -opioid receptor agonists in vivo. We found that following intracerebroventricular injection over a dose range of 1 to 30 µg of both salvinorin A and salvinorinyl-2-propionate produces antinociception in wild-type mice but not in a novel strain of -opioid receptor knockout mice. Moreover, both salvinorin A and salvinorinyl-2-propionate reduce rectal body temperature, similar to conventional -opioid receptor agonists, in a genotype-dependent manner. In addition, we determined that salvinorin A has high affinity for ₁- but not ₂-opioid receptors, demonstrating selectivity for this receptor subclass. Finally, treatment over the same dose range with salvinorin B, which is inactive in vitro, produced neither antinociceptive nor hypothermic effects in wild-type mice. These data demonstrate that salvinorin A is the active component of S. divinorum, selective for ₁-opioid receptors, and that salvinorin A and specific structurally related analogs produce behavioral effects that require the -opioid receptor.

Address correspondence to: Dr. John E. Pintar, Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. E-mail: pintar{at}cabm.rutgers.edu

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