The objective of this Project is to develop selective genetic and pharmacological tools to perturb the major pathways for endocannabinoid (EC) metabolism. These pathways can roughly be divided into four separate groups: 1) anandamide (AEA) biosynthesis, 2) AEA degradation, 3) 2-arachidonoyl (2-AG) biosynthesis, and 4) 2-AG degradation. Among these processes, AEA degradation is the most mature in terms of our scientific understanding and availability of research tools. Studies over the past decade using knockout mice and selective inhibitors have demonstrated that the integral membrane protein fatty acid amide hydrolase (FAAH) is the primary enzyme responsible for terminating AEA signaling in the central nervous system (CMS). In contrast, our understanding of the enzymes involved in the other major branches of EC metabolism is much less complete. Although candidate enzymes have been identified in these pathways, their actual contribution to EC metabolism in vivo remains largely unknown due to a dearth of selective research tools to probe their function in living systems. We plan to address this crucial problem by creating knockout mouse models and selective chemical inhibitors for key enzymes implicated in EC metabolism. These enzymes include: 1) the putative AEA biosynthetic enzymes, a/b-hydrolase 4 (Abh4) and glycerophosphodiesterase-1 (GDE-1), 2) the putative 2-AG degradative enzyme, monoacylgycerol lipase (MAGL), and 3) the putative 2-AG biosynthetic enzyme diacylgycerol lipase-alpha (DAGL-a). Importantly, these research efforts will be bolstered by a set of innovative technologies that will ensure efficient generation of high-quality research tools for rapid dissemination among the Program Project team and larger EC research community. Collectively, the studies described in this Project will generate the requisite genetic and pharmacological tools to systematically delineate the key enzymes involved in all major branches of EC metabolism. The following three major hypotheses will be tested: 1) AEA is biosynthesized by a pathway involving the sequential action of Abhd4 and GDE-1;2) 2-AG catabolism is regulated by multiple enzymes in vivo, with a significant contribution attributable to MAGL;3) 2-AG biosynthesis in the mature brain is predominantly controlled by DAGL-a.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDA1-RXL-E)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
United States
Zip Code
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

Showing the most recent 10 out of 263 publications