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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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
Sticht, Martin A; Limebeer, Cheryl L; Rafla, Benjamin R et al. (2016) Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex. Neuropharmacology 102:92-102
Tessaris, Daniele; Matarazzo, Patrizia; Lala, Roberto et al. (2016) Odontoiatric perspectives and osteonecrosis of the jaw as a possible adverse effect of bisphosphonates therapy in fibrous dysplasia and McCune-Albright syndrome. J Pediatr Endocrinol Metab 29:333-6
Kocova, Mirjana; Zdraveska, Nikolina; Kacarska, Rozana et al. (2016) Diagnostic approach in children with unusual symptoms of acquired hypothyroidism. When to look for pituitary hyperplasia? J Pediatr Endocrinol Metab 29:297-303
Staiano, Rosaria I; Loffredo, Stefania; Borriello, Francesco et al. (2016) Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors. J Leukoc Biol 99:531-40
Buczynski, Matthew W; Herman, Melissa A; Hsu, Ku-Lung et al. (2016) Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. Proc Natl Acad Sci U S A 113:1086-91
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
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
Ignatowska-Jankowska, Bogna M; Baillie, Gemma L; Kinsey, Steven et al. (2015) A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects. Neuropsychopharmacology 40:2948-59
Crowe, Molly S; Leishman, Emma; Banks, Matthew L et al. (2015) Combined inhibition of monoacylglycerol lipase and cyclooxygenases synergistically reduces neuropathic pain in mice. Br J Pharmacol 172:1700-12

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