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1. J Pharmacol Exp Ther. 2012 Mar 20. [Epub ahead of print]

Behavioral effects and CNS levels of the broadly available K-agonist hallucinogen
salvinorin A are affected by p-glycoprotein modulation in vivo.

Butelman E, Caspers M, Lovell KM, Kreek MJ, Prisinzano T.

1 The Rockefeller University;

Active blood-brain barrier mechanisms, such as the major efflux transporter
p-glycoprotein (mdr1) modulate the in vivo/CNS effects of many pharmacological
agents, be they used for non-medical reasons, or in pharmacotherapy. The
powerful, widely available hallucinogen salvinorin A (from the plant Salvia
divinorum), is a high efficacy selective ╬║-opioid agonist, and displays fast
onset behavioral effects (e.g., within 1 minute of administration), and
relatively short duration of action. In vitro studies suggest that salvinorin A
may be a p-glycoprotein substrate, and thus the functional status of
p-glycoprotein may influence the behavioral effects of salvinorin A, or its
residence in CNS following parenteral administration. We therefore studied
whether a competing p-glycoprotein substrate (the clinically available agent
loperamide; 0.032-0.32 mg/kg), or a selective p-glycoprotein blocker tariquidar
(0.32-3.2 mg/kg) could enhance unconditioned behavioral effects (ptosis and
facial relaxation, known to be caused by ╬║agonists in non-human primates) of
salvinorin A, as well as its entry and residence in CNS, as measured by
cerebrospinal fluid sampling. Pretreatment with either loperamide or tariquidar
dose-dependently enhanced salvinorin A-induced ptosis, but not facial relaxation.
In a control study, loperamide and tariquidar were inactive when given as a
pretreatment to U69,593, a ╬║-agonist known to be a very poor p-glycoprotein
substrate. Furthermore, pretreatment with tariquidar (3.2 mg/kg) also enhanced
peak levels of salvinorin A in cerebrospinal fluid, following its i.v.
administration. These are the first studies in vivo showing sensitivity of
salvinorin A effects to modulation by the p-glycoprotein transporter, a major
functional component of the blood-brain barrier.

PMID: 22434677 [PubMed - as supplied by publisher]