Behavioral effects and central nervous system levels of the broadly available κ-agonist hallucinogen salvinorin A are affected by P-glycoprotein modulation in vivo.
Eduardo R Butelman, Michael J Caspers, Kimberly M Lovell, Mary Jeanne Kreek, Thomas E Prisinzano
The Journal of pharmacology and experimental therapeutics June 1, 2012 DOI: 10.1124/jpet.112.193227 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vivo experimental study Peer reviewed |
|---|---|
| Population | Nonhuman primates |
| Interventions | loperamide tariquidar salvinorin A U69 593 |
| Dose | loperamide 0.032-0.32 mg/kg; tariquidar 0.32-3.2 mg/kg; salvinorin A not specified in abstract; U69,593 not specified |
| Topics | Salvia divinorum |
| Keywords | P-glycoprotein Efflux transporter Bbb mechanism Blood-brain barrier mechanism Hallucinogen Pharmacological agent Cns barrier Cns control Cns pharmacology Drug effects In vivo effects Drug transport Pharmacokinetics Behavioral effects Cns levels Cerebrospinal fluid Csf Intravenous administration Modulation Amplification Pretreatment Mechanisms Role |
| Citations | 27 |
| Key findings | P-glycoprotein activity modulates the behavioral effects and CNS entry of salvinorin A, as shown by enhanced ptosis and increased cerebrospinal fluid levels after pretreatment with P-glycoprotein inhibitors. |
Abstract
Active blood-brain barrier mechanisms, such as the major efflux transporter P-glycoprotein (mdr1), modulate the in vivo/central nervous system (CNS) effects of many pharmacological agents, whether they are used for nonmedical reasons or in pharmacotherapy. The powerful, widely available hallucinogen salvinorin A (from the plant Salvia divinorum) is a high-efficacy, selective κ-opioid agonist and displays fast-onset behavioral effects (e.g., within 1 min of administration) and relatively short duration of action. In vitro studies suggest that salvinorin A may be a P-glycoprotein substrate; thus, the functional status of P-glycoprotein may influence the behavioral effects of salvinorin A or its residence in CNS after 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 κ-agonists in nonhuman primates) of salvinorin A, as well as its entry and residence in the 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 ((+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593), a κ-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 after intravenous administration. These are the first studies in vivo showing the sensitivity of salvinorin A effects to modulation by the P-glycoprotein transporter, a major functional component of the blood-brain barrier.