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.
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.
|Gamage, Thomas F; Ignatowska-Jankowska, Bogna M; Wiley, Jenny L et al. (2014) In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569. Behav Pharmacol 25:182-5|
|Dainese, Enrico; De Fabritiis, Gianni; Sabatucci, Annalaura et al. (2014) Membrane lipids are key modulators of the endocannabinoid-hydrolase FAAH. Biochem J 457:463-72|
|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|
|Otrubova, Katerina; Cravatt, Benjamin F; Boger, Dale L (2014) Design, synthesis, and characterization of ?-ketoheterocycles that additionally target the cytosolic port Cys269 of fatty acid amide hydrolase. J Med Chem 57:1079-89|
|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|
|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|
|Naydenov, Alipi V; Horne, Eric A; Cheah, Christine S et al. (2014) ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice. Neuron 83:361-71|
|Buczynski, Matthew W; Polis, Ilham Y; Parsons, Loren H (2013) The volitional nature of nicotine exposure alters anandamide and oleoylethanolamide levels in the ventral tegmental area. Neuropsychopharmacology 38:574-84|
|Chang, Jae Won; Cognetta 3rd, Armand B; Niphakis, Micah J et al. (2013) Proteome-wide reactivity profiling identifies diverse carbamate chemotypes tuned for serine hydrolase inhibition. ACS Chem Biol 8:1590-9|
|Kinsey, Steven G; Wise, Laura E; Ramesh, Divya et al. (2013) Repeated low-dose administration of the monoacylglycerol lipase inhibitor JZL184 retains cannabinoid receptor type 1-mediated antinociceptive and gastroprotective effects. J Pharmacol Exp Ther 345:492-501|
Showing the most recent 10 out of 111 publications