RT Journal Article SR Electronic T1 Antinociceptive and Hypothermic Effects of Salvinorin A Are Abolished in a Novel Strain of κ-Opioid Receptor-1 Knockout Mice JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 641 OP 648 DO 10.1124/jpet.106.101998 VO 318 IS 2 A1 Michael A. Ansonoff A1 Jiwen Zhang A1 Traci Czyzyk A1 Richard B. Rothman A1 Jeremy Stewart A1 Heng Xu A1 Jordan Zjwiony A1 Daniel J. Siebert A1 Feng Yang A1 Bryan L. Roth A1 John E. Pintar YR 2006 UL http://jpet.aspetjournals.org/content/318/2/641.abstract AB 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 κ-opioid receptor. We have examined whether salvinorin A, the C2-substituted derivative salvinorinyl-2-propionate, and salvinorin B can act as κ-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 κ-opioid receptor knockout mice. Moreover, both salvinorin A and salvinorinyl-2-propionate reduce rectal body temperature, similar to conventional κ-opioid receptor agonists, in a genotype-dependent manner. In addition, we determined that salvinorin A has high affinity for κ1- but not κ2-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 κ1-opioid receptors, and that salvinorin A and specific structurally related analogs produce behavioral effects that require the κ-opioid receptor. The American Society for Pharmacology and Experimental Therapeutics