Chemical Probes of Endocannabinoid Metabolism
Open accessAbstract
The endocannabinoid signaling system regulates diverse physiologic processes and has attracted considerable attention as a potential pharmaceutical target for treating diseases, such as pain, anxiety/depression, and metabolic disorders. The principal ligands of the endocannabinoid system are the lipid transmitters N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), which activate the two major cannabinoid receptors, CB1 and CB2. Anandamide and 2-AG signaling pathways in the nervous system are terminated by enzymatic hydrolysis mediated primarily by the serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. In this review, we will discuss the development of FAAH and MAGL inhibitors and their pharmacological application to investigate the function of anandamide and 2-AG signaling pathways in preclinical models of neurobehavioral processes, such as pain, anxiety, and addiction. We will place emphasis on how these studies are beginning to discern the different roles played by anandamide and 2-AG in the nervous system and the resulting implications for advancing endocannabinoid hydrolase inhibitors as next-generation therapeutics.
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Rate-limiting biosynthetic enzyme(s) for AEA production remain to be identified.
“Although several biosynthetic pathways have been proposed for AEA production, rate-limiting biosynthetic enzyme(s) remain to be identified (Blankman and Cravatt, 2013).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Blankman and Cravatt, 2013
ECBs are not stored in readily releasable pools but are rapidly synthesized on-demand upon depolarization-induced calcium increase.
“Unlike most neurotransmitters, however, ECBs are not stored in readily releasable pools, but instead are rapidly synthesized `on-demand' upon depolarization-induced calcium increase.”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [52]
Manipulations that alter FAAH activity, such as stress or administration of compounds targeting FAAH, would be predicted to functionally impact BLA functions, including anxiety.
“By extension, manipulations that lead to alterations in FAAH activity, such as stress or administration of compounds targeting FAAH [52], would be predicted to functionally impact BLA functions, including anxiety.”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [52]
FAAH inhibitors would selectively augment CB1R signaling in neural circuits where AEA was recruited because of the on-demand nature of ECB release.
“The `on-demand' nature of ECB release makes it a particularly attractive target for drug development because FAAH inhibitors would selectively augment CB1R signaling in neural circuits where AEA was recruited [52].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [52]
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References 221 · Cited by 327
Research works printed but not linked: 2
- Blankman and Cravatt Herkenham M (1995) Localization of cannabinoid receptors in brain and periphery, in Cannabinoid Receptors (Pertwee RG, ed) pp 145-166, Academic Press, London.
- Siegel GJ, Agranoff BW, Albers RW, Fisher SK, and Uhler MD, eds, ed (1999) Basic neurochemistry, Lippincott-Raven, Philadelphia.
- Authors
- Blankman, J. L., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- ORCID
- Cravatt, Benjamin F.
- Venue
- Pharmacological Reviews
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 65
- Issue
- 2
- Pages
- 849-871
- ISSN
- 0031-6997 (ISSN-L)
- PMC
- PMC3639726
- OpenAlex
- W2170617040
- Cited by
- 327
- References
- 221
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 13 · 2023: 14 · 2022: 19 · 2021: 23 · 2020: 18 · 2019: 24 · 2018: 24 · 2017: 29 · 2016: 34 · 2015: 45 · 2014: 43 · 2013: 20
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Pharmacological Reviews (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DA017259, DA009789)
- National Institute on Drug Abuse (DA033760, P01DA009789, DA-017259, DA032933, R01DA032933, F31DA026261, R01DA033760, P01DA017259, DA 009789, DA026261)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Keywords
- endocannabinoid system, endocannabinoid metabolism, anandamide, 2-arachidonoylglycerol, fatty acid amide hydrolase, monoacylglycerol lipase, FAAH inhibitors, MAGL inhibitors, cannabinoid receptors, pain, anxiety, addiction
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Arachidonic Acids, Depression, Disease Models, Animal, Enzyme Inhibitors, Glycerides, Humans, Ligands, Monoacylglycerol Lipases, Pain, Molecular Structure, Signal Transduction, Substance-Related Disorders, Polyunsaturated Alkamides, Endocannabinoids
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