TPhreo jeocbt jescutmivme aoryf : Project 1 is to understand the biochemical and cellular mechanisms for terminating endocannabinoid (EC) signaling in the nervous system. The two major ECs, anandamide (AEA) and 2- arachidonoylglycerol (2-AG), are degraded by disfinct enzymatic pathways in vivo. AEA is principally regulated by the integral membrane enzyme fatty acid amide hydrolase (FAAH), which also hydrolyzes several other bioactive fatty acid amides, including the anti-infiammatory lipid A/-palmitoyl ethanolamine, the satiating factor A/-oleoyl ethanolamine, and the TRP channel agonist A/-arachidonoyl taurine. A major challenge in understanding FAAH-regulated fatty acid amide signaling is to discriminate the distinct physiological functions of endogenous FAAH substrates. 2-AG is hydrolyzed by several enzymes in the brain, including the soluble enzyme monoacylglycerol lipase (MAGL) and the integral membrane hydrolases ABHD6 and ABHD12. A major challenge in understanding 2-AG signaling is to determine the unique biochemical and cellular properties of individual 2-AG hydrolytic enzymes. Prior to enzymatic hydrolysis, both AEA and 2-AG may interact with binding proteins responsible for cellular uptake and transport. A major challenge in understanding EC uptake and transport is to identify the putative proteins that mediate these processes. In the previous funding period, we used a combination of synthetic chemistry, enzymology, molecular biology, and functional proteomic/metabolomic methods to enrich our understanding of EC degradative pathways. We have also developed powerful new chemical and genetic tools to probe the function of these pathways. In this renewal application, we plan to use our suite of chemical and genetic tools to gain further mechanistic insights into EC degradative pathways. Specifically, we aim to: 1) characterize mouse models with altered EC degradative pathways, 2) characterize the biochemical and cell biological properties of brain 2-AG hydrolases, and 3) map lipid-protein interactions in EC degradative pathways using chemical proteomic methods. We anticipate that these studies will enhance our understanding of the biochemical pathways that terminate EC signaling in the nervous system and define key components in these pathways that may serve as drug targets for the treatment of a range of human disorders, including pain, depression, and metabolic disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program Projects (P01)
Project #
Application #
Study Section
Human Development Research Subcommittee (NIDA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Wilkerson, Jenny L; Curry, Zachary A; Kinlow, Pamela D et al. (2018) Evaluation of different drug classes on transient sciatic nerve injury-depressed marble burying in mice. Pain 159:1155-1165
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; 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
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 ? 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
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
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

Showing the most recent 10 out of 138 publications