The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.
Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase
Open accessAbstract
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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“AEA and 2-AG are rapidly hydrolyzed by fatty acid amide hydrolase (FAAH) (Cravatt et al, 1996(Cravatt et al, , 2001)), and monoacylglycerol lipase (MAGL) (Dinh et al, 2002), respectively.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Cravatt et al, 2001
In the citing paper
“FAAH-/- mice are hypoalgesic in models of acute and inflammatory pain; these effects are blocked by a CB1 antagonist.29, 30”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [29]
Citations
Cites
Initial sequencing and analysis of the human genome
International Human Genome Sequencing Consortium, Whitehead Institute for Biomedical Research, C. F. G. R., Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., Devon, K., Dewar, K., et al. (2001) · Nature · doi:10.1038/35057062 · Cited by 24,216
The sequence of the human genome
Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., Smith, H. O., Yandell, M., Evans, C. A., Holt, R. A., et al. (2001) · Science · doi:10.1126/science.1058040 · Cited by 13,909
Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor
Devane, W. A., Hanuš, L., Breuer, A., Pertwee, R. G., Stevenson, L. A., Griffin, G., Gibson, D., Mandelbaum, A., Etinger, A., & Mechoulam, R. (1992) · Science · doi:10.1126/science.1470919 · Cited by 5,633
Mechoulam, R., Ben-Shabat, S., Hanus, L., Ligumsky, M., Kaminski, N. E., Schatz, A. R., Gopher, A., Almog, S., Martin, B. R., Compton, D. R., et al. (1995) · Biochemical Pharmacology · doi:10.1016/0006-2952(95)00109-d · Cited by 2,913
Self-citation2-Arachidonoylgylcerol: A Possible Endogenous Cannabinoid Receptor Ligand in Brain
Sugiura, T., Kondo, S., Sukagawa, A., Nakane, S., Shinoda, A., Itoh, K., Yamashita, A., & Waku, K. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.2437 · Cited by 2,196
Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide
Zygmunt, P. M., Petersson, J., Andersson, D. A., Chuang, H.-H., Sørgård, M., Di Marzo, V., Julius, D., & Högestätt, E. D. (1999) · Nature · doi:10.1038/22761 · Cited by 2,142
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
Cravatt, B. F., Giang, D. K., Mayfield, S. P., Boger, D. L., Lerner, R. A., & Gilula, N. B. (1996) · Nature · doi:10.1038/384083a0 · Cited by 2,125
Self-citationSR141716A, a potent and selective antagonist of the brain cannabinoid receptor
Rinaldi, M. L., Barth, F., Héaulme, M., Shire, D. J., Calandra, B., Congy, C., Martinez, S., Maruani, J., Neliat, G., Caput, D., et al. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)00773-x · Cited by 1,762
Formation and inactivation of endogenous cannabinoid anandamide in central neurons
Marzo, V. D., Fontana, A., Cadas, H., Schinelli, S., Cimino, G., Schwartz, J.-C., & Piomelli, D. (1994) · Nature · doi:10.1038/372686a0 · Cited by 1,585
Pharmacology of cannabinoid CB1 and CB2 receptors
Pertwee, R. G. (1997) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(97)82001-3 · Cited by 1,526
Control of pain initiation by endogenous cannabinoids
Calignano, A., Rana, G. L., Giuffrida, A., & Piomelli, D. (1998) · Nature · doi:10.1038/28393 · Cited by 1,069
Functional Role of High-Affinity Anandamide Transport, as Revealed by Selective Inhibition
Beltramo, M., Stella, N., Calignano, A., Lin, S. Y., Makriyannis, A., & Piomelli, D. (1997) · Science · doi:10.1126/science.277.5329.1094 · Cited by 813
Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist
Deutsch, D. G., & Chin, S. A. (1993) · Biochemical Pharmacology · doi:10.1016/0006-2952(93)90486-g · Cited by 706
Chemical characterization of a family of brain lipids that induce sleep
Cravatt, B. F., Prospero-Garcia, O., Siuzdak, G., Gilula, N. B., Henriksen, S. J., Boger, D. L., & Lerner, R. A. (1995) · Science · doi:10.1126/science.7770779 · Cited by 620
Self-citationJárai, Z., Wagner, J. A., Varga, K., Lake, K. D., Compton, D. M., Martin, B. R., Zimmer, A. M., Bonner, T. I., Buckley, N. E., Mezey, É., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.24.14136 · Cited by 597
Self-citationPrimary afferent tachykinins are required to experience moderate to intense pain
Cao, Y. Q., Mantyh, P. W., Carlson, E. J., Gillespie, A.-M., Epstein, C. J., & Basbaum, A. I. (1998) · Nature · doi:10.1038/32897 · Cited by 595
Pain modulation by release of the endogenous cannabinoid anandamide
Walker, J. M., Huang, S. M., Strangman, N. M., Tsou, K., & Sañudo-Peña, M. C. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.21.12198 · Cited by 486
Felder, C. C., Briley, E. M., Axelrod, J., Simpson, J. T., Mackie, K., & Devane, W. A. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.16.7656 · Cited by 478
Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent
Fride, E., & Mechoulam, R. (1993) · European Journal of Pharmacology · doi:10.1016/0014-2999(93)90468-w · Cited by 448
Molecular characterization of human and mouse fatty acid amide hydrolases
Giang, D. K., & Cravatt, B. F. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.6.2238 · Cited by 429
Self-citationThe endocannabinoid system as a target for therapeutic drugs
Piomelli, D., Giuffrida, A., Calignano, A., & Rodrı́guez de Fonseca, F. (2000) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(00)01482-6 · Cited by 421
Marzo, V. D., Breivogel, C. S., Tao, Q., Bridgen, D. T., Razdan, R. K., Zimmer, A. M., Zimmer, A., & Martin, B. R. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0752434.x · Cited by 394
Self-citationThe pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice.
Smith, P. B., Compton, D. M., Welch, S. P., Razdan, R. K., Mechoulam, R., & Martin, B. R. (1994) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)22356-4 · Cited by 394
Self-citationVenance, L., Piomelli, D., Glowinski, J., & Glaume, C. (1995) · Nature · doi:10.1038/376590a0 · Cited by 351
Egertová, M., Giang, D. K., Cravatt, B. F., & Elphick, M. R. (1998) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1998.0543 · Cited by 337
Self-citationAnandamide Amidohydrolase Activity in Rat Brain Microsomes
Desarnaud, F., Cadas, H., & Piomelli, D. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.11.6030 · Cited by 336
Cannabinoids as Therapeutic Agents
(2019) · Chapman & Hall/CRC eBooks · doi:10.1201/9780429260667 · Cited by 311
Ueda, N., Kurahashi, Y., Yamamoto, S., & Tokunaga, T. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.40.23823 · Cited by 303
Boger, D. L., Sato, H., Lerner, A. E., Hedrick, M. P., Fecik, R. A., Miyauchi, H., Wilkie, G. D., Austin, B. J., Patricelli, M. P., & Cravatt, B. F. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.10.5044 · Cited by 272
Self-citationTsou, K., Nogueron, M. I., Muthian, S., Sañudo-Peña, M. C., Hillard, C. J., Deutsch, D. G., & Walker, J. M. (1998) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00700-9 · Cited by 240
Crawley, J. N., Corwin, R. L., Robinson, J. K., Felder, C. C., Devane, W. A., & Axelrod, J. (1993) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(93)90230-q · Cited by 236
Terranova, J.-P., Michaud, J.-C., Fur, G. L., & Soubrié, P. (1995) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/bf00169393 · Cited by 206
Discovery and characterization of endogenous cannabinoids
Martin, B. R., Mechoulam, R., & Razdan, R. K. (1999) · Life Sciences · doi:10.1016/s0024-3205(99)00281-7 · Cited by 205
Self-citationMaurelli, S., Bisogno, T., PETROCELLIS, L. D., Luccia, A. D., Marino, G., & Marzo, V. D. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)01311-3 · Cited by 200
Effects of anandamide on cannabinoid receptors in rat brain membranes
Childers, S. R., Sexton, T., & Roy, M. B. (1994) · Biochemical Pharmacology · doi:10.1016/0006-2952(94)90134-1 · Cited by 176
Adams, I. B., Compton, D. M., & Martin, B. R. (1998) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37342-2 · Cited by 165
Self-citationThe Biodisposition and Metabolism of Anandamide in Mice
Willoughby, K. A., Moore, S. F., Martin, B. R., & Ellis, E. F. (1997) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)36812-0 · Cited by 159
Self-citationPatricelli, M. P., Lovato, M. A., & Cravatt, B. F. (1999) · Biochemistry · doi:10.1021/bi990637z · Cited by 152
Self-citationPatricelli, M. P., Lashuel, H. A., Giang, D. K., Kelly, J. W., & Cravatt, B. F. (1998) · Biochemistry · doi:10.1021/bi981733n · Cited by 147
Self-citationAn acid amidase hydrolyzing anandamide as an endogenous ligand forcannabinoid receptors
Ueda, N., Yamanaka, K., Terasawa, Y., & Yamamoto, S. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00820-0 · Cited by 100
Cannabinoids, endogenous ligands and synthetic analogs
Pop, E. (1999) · Current Opinion in Chemical Biology · doi:10.1016/s1367-5931(99)80062-3 · Cited by 45
Costa, B., Vailati, S., & Colleoni, M. (1999) · Behavioural Pharmacology · doi:10.1097/00008877-199905000-00009 · Cited by 44
Flagged first, then by citations
Research works printed but not linked: 3
- P B Smith, D R Compton, S P Welch, R K Razdan, R Mechoulam, B R Martin J Pharmacol Exp Ther 270, 219–227 (1994).
- I B Adams, D R Compton, B R Martin J Pharmacol Exp Ther 284, 1209–1217 (1998).
- K A Willoughby, S F Moore, B R Martin, E F Ellis J Pharmacol Exp Ther 282, 243–247 (1997).
Cited by
Sorted by citations
International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors
Howlett, A. C., Barth, F., Bonner, T. I., Cabral, G., Casellas, P., Devane, W. A., Felder, C. C., Herkenham, M., Mackie, K., Martin, B. R., et al. (2002) · Pharmacological Reviews · doi:10.1124/pr.54.2.161 · Cited by 2,819
Self-citationThe Endocannabinoid System as an Emerging Target of Pharmacotherapy
Pacher, P., Bátkai, S., & Kunos, G. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.3.2 · Cited by 2,077
The molecular logic of endocannabinoid signalling
Piomelli, D. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1247 · Cited by 1,957
Brain monoglyceride lipase participating in endocannabinoid inactivation
Dinh, T. P., Carpenter, D., Leslie, F. M., Freund, T. F., Katona, I., Sensi, S. L., Kathuria, S., & Piomelli, D. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.152334899 · Cited by 1,373
Modulation of anxiety through blockade of anandamide hydrolysis
Kathuria, S., Gaetani, S., Fegley, D., Valiño, F., Duranti, A., Tontini, A., Mor, M., Tarzia, G., Rana, G. L., Calignano, A., et al. (2003) · Nature Medicine · doi:10.1038/nm803 · Cited by 1,293
Metadata
- 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)
- 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
- 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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