The primary objectives of this Program Project are to establish the functional roles of the endocannabinoid system in normal physiological processes and in abnormal or disease states and to determine the extent to which it serves as a mediator in the effects of exogenous cannabinoids. It is our premise that understanding the endogenous cannabinoid system will allow us to address public health issues regarding drugs of abuse as well as co-morbidities that include cognitive disorders, compulsive behavior, pain, motor dysfunction and numerous peripheral disorders. Incredible progress in the past decade has firmly established the existence and homeostatic importance of the endocannabinoid system and its key components (receptor subtypes, endogenous ligands, synthetic and metabolic pathways, signaling pathways, etc.) As with most biological systems, as knowledge accumulates so does the level of complexity. We have assembled a team of chemists (Mechoulam, Razdan and Mahadevan), biochemists and molecular biologists (Cravatt and Di Marzo), and pharmacologists (Martin, Wiley, Lichtman, Pertwee, and Ross) who will address fundamental questions related to distinguishing between the physiological functions of anandamide (AEA) and 2- arachidonoylglycerol (2-AG), investigating whether other endocannabinoids exist, and determining the relationship between the roles of endocannabinoids in neural processes (e.g., pain, reward, neuroprotection) and peripheral processes (e.g., bone formation, inflammation). Our approach involves synthesis of putative endocannabinoids, stable and potent analogs, metabolic and synthetic enzyme inhibitors and CB1 receptor allosteric modulators. Furthermore, we will manipulate enzymes that are putatively responsible for AEA and 2-AG synthesis and degradation as well as establish the resulting lipid profiles using liquid chromatography, ion trap, time-of-flight mass spectrometry to identify new lipid entities associated with the endocannabinoid system. Dr. Cravatt will systematically delete existing as well as proposed synthetic and metabolic enzymes for AEA and 2-AG in mice. These genetically modified animals, along with the synthetic probes and newly discovered endocannabinoids, will be used to further elucidate the function of the endocannabinoid system in neuropathic and inflammatory pain, neurotrauma, reward, and dependence-related events. Ultimately, the knowledge gained from this basic research will yield novel therapeutic targets that can be exploited with the pharmacological agents developed here. PROGRAM CHARACTERISTICS

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program Projects (P01)
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Special Emphasis Panel (ZDA1-RXL-E (19))
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Rapaka, Rao
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Virginia Commonwealth University
Schools of Medicine
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Yun, Bogeon; Lee, HeeJung; Ghosh, Moumita et al. (2014) Serine hydrolase inhibitors block necrotic cell death by preventing calcium overload of the mitochondria and permeability transition pore formation. J Biol Chem 289:1491-504
Galdino, Giovane; Romero, Thiago; Silva, José Felippe Pinho da et al. (2014) Acute resistance exercise induces antinociception by activation of the endocannabinoid system in rats. Anesth Analg 119:702-15
Pertwee, Roger G (2014) Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications. Proc Nutr Soc 73:96-105
Vallée, Monique; Vitiello, Sergio; Bellocchio, Luigi et al. (2014) Pregnenolone can protect the brain from cannabis intoxication. Science 343:94-8
Ignatowska-Jankowska, B M; Ghosh, S; Crowe, M S et al. (2014) In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects. Br J Pharmacol 171:1392-407
Abdulnour, Joseph; Yasari, Siham; Rabasa-Lhoret, Remi et al. (2014) Circulating endocannabinoids in insulin sensitive vs. insulin resistant obese postmenopausal women. A MONET group study. Obesity (Silver Spring) 22:211-6
Grim, Travis W; Ghosh, Sudeshna; Hsu, Ku-Lung et al. (2014) Combined inhibition of FAAH and COX produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models. Pharmacol Biochem Behav 124:405-11
Wiley, Jenny L; Walentiny, D Matthew; Wright Jr, M Jerry et al. (2014) Endocannabinoid contribution to ?9-tetrahydrocannabinol discrimination in rodents. Eur J Pharmacol 737:97-105
Schlosburg, Joel E; Kinsey, Steven G; Ignatowska-Jankowska, Bogna et al. (2014) Prolonged monoacylglycerol lipase blockade causes equivalent cannabinoid receptor type 1 receptor-mediated adaptations in fatty acid amide hydrolase wild-type and knockout mice. J Pharmacol Exp Ther 350:196-204
Murase, Ryuichi; Kawamura, Rumi; Singer, Eric et al. (2014) Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer. Br J Pharmacol 171:4464-77

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