Pharmacological characterization of the novel kappa opioid agonist Salvinorin A in the mouse


K.M. Kugle, L.J. Valdes, J.H. Woods, J.R. Traynor, and W.E. Fantegrossi
The University of Michigan, Ann Arbor, MI

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This is the abstract of a poster session presented at the 2004 meeting of The College on Problems of Drug Dependence (CPDD), in San Juan, Puerto Rico.


Abstract
Salvinorin A is a psychoactive compound derived from the leaves of the Mexican mint Salvia divinorum. Anecdotal reports from human users describe this compound as hallucinogenic, but previous research has not detected any appreciable affinity at hallucinogen-related serotonin receptors. Further research demonstrated that salvinorin A binds with high affinity and efficacy at kappa opioid receptors, but few in vivo studies have characterized this novel compound. We investigated the actions of salvinorin A using the inverted screen test in mice. Specifically, we compared salvinorin A with the short-acting mu agonist remifentanil, and the classical kappa agonist U69,593. Similar to U69,593 and remifentanil, salvinorin A rapidly induced a profound, but short-term, sedation. The sedative effects of salvinorin A and U69,593 were blocked by prior administration of the kappa antagonist nor-binaltorphimine, but not by a mu-selective dose of naloxone or a delta-selective dose of naltrindole. In contrast, the sedative effects of remifentanil were blocked by naloxone, but not naltrindole or nor-binaltorphimine. In further experiments, both U69,593 and salvinorin A stimulated GTPgammaS binding in the rodent brain with equivalent potency and efficacy. These results suggest that salvinorin A is active in vivo at kappa opioid receptors, and is equivalent with U69,593 in terms of potency and efficacy in agonist-stimulated GTPgammaS binding in rodent brain. These studies were supported by USPHS grant DA00254.