The mammalian fatty acid amides and fatty acyl glycerol have been directly linked to the regulation of pain thresholds, body temperature, sleep cycles, appetite, and higher-level cognitive processes such as memory and learning. Nonetheless, how these lipids influence nervous system function is poorly understood. While some of these molecules trigger the central cannabinoid receptors CB1 and CB2, other members of this class lack described molecular targets. The enzyme fatty acid amide hydrolase (FAAH) controls the levels of fatty acid amides in vivo, setting the baseline function of their various corresponding physiologies. We have determined the three dimensional structure of this integral membrane protein in complex with novel inhibitors, and we are now prepared to expand these structure determination efforts to extend our knowledge of the mechanisms of action of this important enzyme. The studies described in this application (Project 2 of the Program Project) aim to determine higher resolution FAAH structures, as well as structures of human FAAH, apo-FAAH, and FAAH-inhibitor/product complexes. Furthermore, we will begin studies to solve the structure of the monoacylglycerol lipase which degrades neuronal 2-arachidonyl glycerol to complement our understanding of endocannabinoid metabolism. Information accrued from our studies will not only enlighten our understanding of these key enzymes but will also serve as a guide for the development of agents designed to intersect the endocannabinoid system in vivo, possibly to therapeutic benefit.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA017259-09
Application #
8375149
Study Section
Human Development Research Subcommittee (NIDA)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$227,107
Indirect Cost
$108,000
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Wilkerson, Jenny L; Ghosh, Sudeshna; Mustafa, Mohammed et al. (2017) The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice. Neuropharmacology 114:156-167
Wilkerson, Jenny L; Donvito, Giulia; Grim, Travis W et al. (2017) Investigation of Diacylglycerol Lipase Alpha Inhibition in the Mouse Lipopolysaccharide Inflammatory Pain Model. J Pharmacol Exp Ther 363:394-401
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, 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
Wilkerson, J L; Ghosh, S; Bagdas, D et al. (2016) Diacylglycerol lipase ? inhibition reverses nociceptive behaviour in mouse models of inflammatory and neuropathic pain. Br J Pharmacol 173:1678-92
Muldoon, P P; Chen, J; Harenza, J L et al. (2015) Inhibition of monoacylglycerol lipase reduces nicotine withdrawal. Br J Pharmacol 172:869-82
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
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
Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A et al. (2015) ?9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice. J Pharmacol Exp Ther 352:195-207
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

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