Cited by 1,310Cannabis and Cannabinoid ResearchPain Mechanisms and TreatmentsEicosanoids and Hypertension Pharmacology

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Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase

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Cravatt, Benjamin F., Demarest, Kristin, Patricelli, Matthew P., Bracey, Michael H., Giang, Dan K., Martin, Billy R., Lichtman, Aron H.·2001·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.161191698PMC PMC55427

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Abstract

The medicinal properties of marijuana have been recognized for centuries, but clinical and societal acceptance of this drug of abuse as a potential therapeutic agent remains fiercely debated. An attractive alternative to marijuana-based therapeutics would be to target the molecular pathways that mediate the effects of this drug. To date, these neural signaling pathways have been shown to comprise a cannabinoid receptor (CB 1 ) that binds the active constituent of marijuana, tetrahydrocannabinol (THC), and a postulated endogenous CB 1 ligand anandamide. Although anandamide binds and activates the CB 1 receptor in vitro , this compound induces only weak and transient cannabinoid behavioral effects in vivo , possibly a result of its rapid catabolism. Here we show that mice lacking the enzyme fatty acid amide hydrolase (FAAH −/− ) are severely impaired in their ability to degrade anandamide and when treated with this compound, exhibit an array of intense CB 1 -dependent behavioral responses, including hypomotility, analgesia, catalepsy, and hypothermia. FAAH −/− -mice possess 15-fold augmented endogenous brain levels of anandamide and display reduced pain sensation that is reversed by the CB 1 antagonist SR141716A. Collectively, these results indicate that FAAH is a key regulator of anandamide signaling in vivo , setting an endogenous cannabinoid tone that modulates pain perception. FAAH may therefore represent an attractive pharmaceutical target for the treatment of pain and neuropsychiatric disorders.

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Authors: Cravatt, B. F., Demarest, K., Patricelli, M. P., Bracey, M. H., Giang, D. K., Martin, B. R., & Lichtman, A. H.
Affiliations: Scripps Research Institute (US)
ORCID: Cravatt, Benjamin F.
Patricelli, Matthew P.
Lichtman, Aron H.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2001-07-24
Volume: 98
Issue: 16
Pages: 9371-9376
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.161191698
PMC: PMC55427
OpenAlex: W2043033522
Cited by: 1,310
References: 42
Citations by year: 2026: 16 · 2025: 29 · 2024: 28 · 2023: 30 · 2022: 45 · 2021: 33 · 2020: 32 · 2019: 32 · 2018: 43 · 2017: 54 · 2016: 50 · 2015: 49 · 2014: 72 · 2013: 61 · 2012: 68
FWCI: 34.29
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Mental Health (MH58542, R01MH058542)
National Institute on Drug Abuse (R01DA013173, P01DA009789, DA‐03672, DA 09789, DA 131173)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
Keywords: anandamide, fatty acid amide hydrolase, CB1 receptor, endocannabinoid system, cannabinoid receptor signaling, pain perception, analgesia, catalepsy, hypothermia, hypomotility, SR141716A, cannabinoid receptor antagonists, pharmacological pain management
MeSH terms: Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Arachidonic Acids, Behavior, Animal, Brain, Cannabinoids, Ethanolamines, Receptors, Drug, Signal Transduction, Pain Threshold, Mice, Knockout, Receptors, Cannabinoid, Mice, Polyunsaturated Alkamides, Endocannabinoids

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Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase

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