The endocannabinoids (ECs) A/-arachidonoyl ethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) are lipid transmitters that activate the central and peripheral cannabinoid receptors (CB1 and CB2, respectively) to regulate a broad range of physiological processes, including pain sensation, inflammation, cognition, emotional state, and feeding. The magnitude and duration of EC signaling are tightly regulated by hydrolytic enzymes. However, our understanding of the distinct biochemical pathways that terminate AEA and 2-AG signaling in vivo remains incomplete. Key outstanding questions include: 1) what are the mechanisms and three-dimensional structures of EC hydrolases? 2) what are the neurochemical and physiological consequences of perturbing the function of EC hydrolases in vivo? 3) do multiple hydrolases coordinately control 2-AG metabolism in vivo? and 4) do AEA- and 2-AG-dependent EC pathways regulate distinct mammalian behaviors? In this Program Project, we have assembled a multidisciplinary research team that aims to address these questions by developing and implementing cutting-edge chemical, enzymological, genetic, proteomic, structural, and behavioral pharmacology methods. Specifically, we plan to: 1) characterize the biochemical and cellular mechanisms for terminating EC signaling the nervous system (Project 1), 2) determine the crystal structures of key EC hydrolases, including apo-enzymes, inhibitor complexes, and active-site mutants (Project 2), and 3) evaluate the neurochemical and behavioral effects of disrupting EC hydrolases in vivo (Projects 3 and 4). The knowledge gained from these studies will be further applied towards the design of increasingly potent and selective inhibitors of EC hydrolases (Core), which should prove of great value as both research tools and potential therapeutic agents for the treatment of a range of human diseases, including chronic pain, depression, anxiety, and metabolic disorders..

Public Health Relevance

The endogenous cannabinoid system regulates a broad range of neurophysiological processes. Elucidation of the enzymes that regulate endogenous cannabinoids and their mechanisms of action may lead to the identification of new therapeutic targets for the treatment of human disorders such as chronic pain, depression, and anxiety.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA017259-10
Application #
8484799
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Rapaka, Rao
Project Start
2004-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2013
Total Cost
$1,120,904
Indirect Cost
$437,321
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Wills, Kiri L; Petrie, Gavin N; Millett, Geneva et al. (2016) Double Dissociation of Monoacylglycerol Lipase Inhibition and CB1 Antagonism in the Central Amygdala, Basolateral Amygdala, and the Interoceptive Insular Cortex on the Affective Properties of Acute Naloxone-Precipitated Morphine Withdrawal in Rats. Neuropsychopharmacology 41:1865-73
Wilkerson, J L; Ghosh, S; Bagdas, D et al. (2016) Diacylglycerol lipase β inhibition reverses nociceptive behaviour in mouse models of inflammatory and neuropathic pain. Br J Pharmacol 173:1678-92
Wilkerson, Jenny L; Niphakis, Micah J; Grim, Travis W et al. (2016) The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model. J Pharmacol Exp Ther 357:145-56
Gamage, Thomas F; Ignatowska-Jankowska, Bogna M; Muldoon, Pretal P et al. (2015) Differential effects of endocannabinoid catabolic inhibitors on morphine withdrawal in mice. Drug Alcohol Depend 146:7-16
Dincheva, Iva; Drysdale, Andrew T; Hartley, Catherine A et al. (2015) FAAH genetic variation enhances fronto-amygdala function in mouse and human. Nat Commun 6:6395
Ghosh, Sudeshna; Kinsey, Steven G; Liu, Qing-Song et al. (2015) Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice. J Pharmacol Exp Ther 354:111-20
Muldoon, P P; Chen, J; Harenza, J L et al. (2015) Inhibition of monoacylglycerol lipase reduces nicotine withdrawal. Br J Pharmacol 172:869-82
Nass, Sara R; Long, Jonathan Z; Schlosburg, Joel E et al. (2015) Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge. J Neuroimmune Pharmacol 10:364-70
Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A et al. (2015) Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice. J Pharmacol Exp Ther 352:195-207
Gamage, Thomas F; Ignatowska-Jankowska, Bogna M; Wiley, Jenny L et al. (2014) In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569. Behav Pharmacol 25:182-5

Showing the most recent 10 out of 134 publications