Salvinorin A - the active ingredient of the hallucinogenic sage Salvia divinorum - along with Salvia divinorum represent emerging drugs of abuse in the US and elsewhere. Salvinorin A and extracts of Salvia divinorum induce an intense and short-lived hallucinatory experience in humans unlike that of the classical hallucinogens LSD, psilocybin and mescaline. In 2002, my lab discovered that salvinorin A potently and specifically targets ?-opioid receptors (KOR) (Roth et al., PNAS 2002);these findings have been widely replicated. Despite intensive interest in the actions of salvinorin A, we still do not fully understand the molecular and atomic mechanisms responsible for its exquisite potency and selectivity at KOR. The goal of these studies is to discover how salvinorin A binds to and activates KOR. To accomplish these goals we will conduct two specific aims: (1) elucidate the structural features of ?-opioid receptors essential for salvinorin A's actions using high-throughput molecular biology and (2) elucidate the structural features of ?-opioid receptors responsible for salvinorin A's actions via direct biochemical approaches. These studies will clarify how this drug of abuse exerts its actions at the atomic level. These studies are significant as follows: Conceptual: Salvinorin A is an emerging drug of abuse which has profound effects on human perception. Salvinorin A exerts these actions via potent and selective activation of ?-opioid receptors. Understanding how salvinorin A achieves its remarkable selectivity and potency for KORs is an essential first step toward elucidating the mechanism of action of salvinorin A. Technical: We will utilize novel and extraordinarily robust yeast-based technologies we have invented (Armbruster et al., 2007a) to identify the molecular and atomic mechanisms by which salvinorin A binds to and activates KORs. We will also employ newly synthesized pM-affinity and irreversible salvinorin A analogues to identify residues on KOR responsible for binding. To our knowledge, these will be the first studies in the opioid receptor field to biochemically identify residues in the binding pocket.

Public Health Relevance

Salvia divinorum and its active ingredient salvinorin A represent emerging drugs of abuse in the US. These studies could lead to novel treatments for drug abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017204-08
Application #
8213526
Study Section
Special Emphasis Panel (ZRG1-MDCN-G (02))
Program Officer
Hillery, Paul
Project Start
2003-09-30
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
8
Fiscal Year
2012
Total Cost
$323,294
Indirect Cost
$58,146
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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