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.
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.
| Che, Tao; Majumdar, Susruta; Zaidi, Saheem A et al. (2018) Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor. Cell 172:55-67.e15 |
| Manglik, Aashish; Lin, Henry; Aryal, Dipendra K et al. (2016) Structure-based discovery of opioid analgesics with reduced side effects. Nature 537:185-190 |
| Grace, Peter M; Strand, Keith A; Galer, Erika L et al. (2016) Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A 113:E3441-50 |
| Bruchas, Michael R; Roth, Bryan L (2016) New Technologies for Elucidating Opioid Receptor Function. Trends Pharmacol Sci 37:279-289 |
| Roth, Bryan L (2016) DREADDs for Neuroscientists. Neuron 89:683-94 |
| Robinson, J Elliott; Vardy, Eyal; DiBerto, Jeffrey F et al. (2015) Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism. Neuropsychopharmacology 40:2614-22 |
| Huang, Xi-Ping; Karpiak, Joel; Kroeze, Wesley K et al. (2015) Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65. Nature 527:477-83 |
| Vardy, Eyal; Robinson, J Elliott; Li, Chia et al. (2015) A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior. Neuron 86:936-946 |
| Fenalti, Gustavo; Zatsepin, Nadia A; Betti, Cecilia et al. (2015) Structural basis for bifunctional peptide recognition at human ?-opioid receptor. Nat Struct Mol Biol 22:265-8 |
| White, Kate L; Robinson, J Elliott; Zhu, Hu et al. (2015) The G protein-biased ?-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo. J Pharmacol Exp Ther 352:98-109 |
Showing the most recent 10 out of 65 publications
