Fatty acid amide hydrolase (FAAH) is the enzyme predominantly responsible for the catabolism of several fatty acid amides (FAA), including the endogenous cannabinoid N-arachidonoyI ethanolamine (anandamide), the sleep-inducing agent oleamide, the food-suppressing compound N-oleoylethanolamine (OEA), and the peripheral pain-suppressing agent N-palmitoylethanolamine (PEA). The creation of genetically engineered mice that lack this enzyme (i.e., FAAH(-/-) mice) has provided a powerful model to evaluate the function of this enzyme. These mice exhibit a CBI-mediated reduction in pain sensitivity, accompanied by substantial increases in endogenous anandamide levels compared to wild type mice. In the studies proposed in this application, we will evaluate the in vivo effects of a series of highly selective and reversible FAAH inhibitors. These FAAH inhibitors provide complementary tools to further our understanding of the physiological functions of the FAAH/FAA system. This project will employ pharmacological and behavioral methods to address three Specific Aims: 1) To determine the role of endocannabinoid-metabolizing enzymes in acute and chronic pain;2) To determine the role of endocannabinoid-metabolizing enzymes in cognition and emotion;and 3) To determine the role of endocannabinoid-metabolizing enzymes in morphine reward and withdrawal.

Public Health Relevance

The endogenous cannabinoid system regulates a broad range of neurophysiological processes. Elucidation of the enzymes that regulate endogenous cannabinoids and their mechanisms of action may lead to the identification of new therapeutic targets for the treatment of human disorders such as chronic pain, depression, and anxiety.

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
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
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
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

Showing the most recent 10 out of 138 publications