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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 3, 2006; DOI: 10.1124/jpet.106.101998

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Received for publication January 30, 2006.
Revised May 1, 2006.
Accepted for publication May 2, 2006.

Antinociceptive and hypothermic effects of salvinorin A are abolished in a novel strain of KOR-1 KO mice

Michael A Ansonoff 1, Jiwen Zhang 2, Traci Czyzyk 2, Richard B Rothman 3, Jeremy Stewart 4, Heng Xu 3, Jordan Zjawiony 4, Daniel J Siebert 5, Feng Yan 4, Bryan L Roth 4, John E Pintar 2*

1 UMDNJ-Robert Wood Johnson Medical School 2 UMDNJ-Robert Wood Johnson 3 Intramural Research Program, National Institute on Drug Abuse 4 Case Western Reserve University 5 None

* Address correspondence to: E-mail: pintar{at}cabm.rutgers.edu

Abstract

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 {kappa}-opioid receptor. We have examined whether salvinorin A, the C2-substituted derivative salvinorinyl-2-propionate, and salvinorin B can act as {kappa}-opioid receptor agonists in vivo. We found that following intracerebroventricular injection over a dose range of 1-30 µg both salvinorin A and salvinorinyl-2-propionate produce antinociception in wild-type mice, but not in a novel strain of {kappa}-opioid receptor knockout mice. Moreover, both salvinorin A and salvinorinyl-2-propionate reduce rectal body temperature, similar to conventional {kappa}-opioid receptor agonists, in a genotype-dependent manner. Additionally, we determined that salvinorin A has high affinity for {kappa}1 opioid receptors but not {kappa}2 opioid receptors, demonstrating selectivity for {kappa}1 opioid receptors. Finally, treatment over the same dose range with salvinorin B, where it 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 {kappa}1 opioid receptors, and that salvinorin A and specific structurally related analogues produce behavioral effects that require the {kappa}-opioid receptor.


Key words: Knockout, Nociception, Opioid, Salvinorin, Tail flick, Temperature


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