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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
AEA is rapidly hydrolyzed by FAAH.
“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
FAAH-/- mice are hypoalgesic in models of acute and inflammatory pain, and these effects are blocked by a CB1 antagonist.
“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]
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 1,751 · see citing works
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 · see citing works
Pharmacology of cannabinoid CB1 and CB2 receptors
Pertwee, R. G. (1997) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(97)82001-3 · Cited by 1,489 · see citing works
Control of pain initiation by endogenous cannabinoids
Calignano, A., Rana, G. L., Giuffrida, A., & Piomelli, D. (1998) · Nature · doi:10.1038/28393 · Cited by 1,055 · see citing works
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 · see citing works
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 705 · see citing works
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 · see citing works
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 598 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 453 · see citing works
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 · see citing works
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 · see citing works
The 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 · see citing works
Self-citationMarzo, 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 389 · see citing works
Self-citationVenance, L., Piomelli, D., Glowinski, J., & Glaume, C. (1995) · Nature · doi:10.1038/376590a0 · Cited by 352 · see citing works
Anandamide 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 · see citing works
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 333 · see citing works
Self-citationCannabinoids as Therapeutic Agents
(2019) · Chapman & Hall/CRC eBooks · doi:10.1201/9780429260667 · Cited by 311 · see citing works
Ueda, N., Kurahashi, Y., Yamamoto, S., & Tokunaga, T. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.40.23823 · Cited by 303 · see citing works
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 · see citing works
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 · see citing works
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 231 · see citing works
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 · see citing works
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 201 · see citing works
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 · see citing works
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 · see citing works
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 164 · see citing works
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 · see citing works
Self-citationPatricelli, M. P., Lovato, M. A., & Cravatt, B. F. (1999) · Biochemistry · doi:10.1021/bi990637z · Cited by 148 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Costa, B., Vailati, S., & Colleoni, M. (1999) · Behavioural Pharmacology · doi:10.1097/00008877-199905000-00009 · Cited by 44 · see citing works
Flagged first, then by citations
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 · see citing works
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 · see citing works
The molecular logic of endocannabinoid signalling
Piomelli, D. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1247 · Cited by 1,957 · see citing works
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 · see citing works
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 · see citing works
Activity-Based Protein Profiling: From Enzyme Chemistry to Proteomic Chemistry
Cravatt, B. F., Wright, A. T., & Kozarich, J. W. (2008) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.75.101304.124125 · Cited by 1,270 · see citing works
Self-citationThe endocannabinoid system and its therapeutic exploitation
Marzo, V. D., Bifulco, M., & Petrocellis, L. D. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1495 · Cited by 1,090 · see citing works
Endocannabinoid Hydrolysis Generates Brain Prostaglandins That Promote Neuroinflammation
Nomura, D. K., Morrison, B. E., Blankman, J. L., Long, J. Z., Kinsey, S. G., Marcondes, M. C. G., Ward, A. M., Hahn, Y. K., Lichtman, A. H., Conti, B., et al. (2011) · Science · doi:10.1126/science.1209200 · Cited by 727 · see citing works
Self-citationStructure and function of fatty acid amide hydrolase
McKinney, M. K., & Cravatt, B. F. (2005) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.082803.133450 · Cited by 680 · see citing works
Self-citationChronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system
Schlosburg, J. E., Blankman, J. L., Long, J. Z., Nomura, D. K., Pan, B., Kinsey, S. G., Nguyen, P. T., Ramesh, D., Booker, L., Burston, J. J., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2616 · Cited by 641 · see citing works
Self-citationAdipose triglyceride lipase and the lipolytic catabolism of cellular fat stores.
Zechner, R., Kienesberger, P. C., Haemmerle, G., Zimmermann, R., & Lass, A. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800031-jlr200 · Cited by 576 · see citing works
Gulyas, A. I., Cravatt, B. F., Bracey, M. H., Dinh, T. P., Piomelli, D., Boscia, F., & Freund, T. F. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03428.x · Cited by 561 · see citing works
Self-citationCannabinoids as Novel Anti-Inflammatory Drugs
Nagarkatti, P., Pandey, R., Rieder, S. A., Hegde, V. L., & Nagarkatti, M. (2009) · Future Medicinal Chemistry · doi:10.4155/fmc.09.93 · Cited by 555 · see citing works
“Fatty acid amide hydrolase is the major enzyme involved in the degradation of several bioactive fatty amides, in particular anandamide [11], and its genetic deletion in mice leads to a strongly decreased ability to degrade this endocannabinoid and an increase of anandamide levels in several tissues [66].”
Enzymatic pathways that regulate endocannabinoid signaling in the nervous system
Ahn, K., McKinney, M. K., & Cravatt, B. F. (2008) · Chemical Reviews · doi:10.1021/cr0782067 · Cited by 529 · see citing works
Self-citationGao, Y., Vasilyev, D. V., Goncalves, M. B., Howell, F. V., Hobbs, C., Reisenberg, M., Shen, R., Zhang, M.-Y., Strassle, B. W., Lu, P., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5693-09.2010 · Cited by 473 · see citing works
Högestätt, E. D., Jönsson, B. A. G., Ermund, A., Andersson, D. A., Björk, H., Alexander, J. P., Cravatt, B. F., Basbaum, A. I., & Zygmunt, P. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501489200 · Cited by 454 · see citing works
Self-citationDiscovery and Characterization of a Highly Selective FAAH Inhibitor that Reduces Inflammatory Pain
Ahn, K., Johnson, D. S., Mileni, M., Beidler, D., Long, J. Z., McKinney, M. K., Weerapana, E., Sadagopan, N., Liimatta, M., Smith, S. E., et al. (2009) · Chemistry & Biology · doi:10.1016/j.chembiol.2009.02.013 · Cited by 439 · see citing works
Self-citationFegley, D., Gaetani, S., Duranti, A., Tontini, A., Mor, M., Tarzia, G., & Piomelli, D. (2005) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.078980 · Cited by 427 · see citing works
Enhancing Cannabinoid Neurotransmission Augments the Extinction of Conditioned Fear
Chhatwal, J. P., Davis, M., Maguschak, K. A., & Ressler, K. J. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300655 · Cited by 376 · see citing works
Huggins, J. P., Smart, T. S., Langman, S., Taylor, L., & Young, T. (2012) · Pain · doi:10.1016/j.pain.2012.04.020 · Cited by 375 · see citing works
Egertová, M., Cravatt, B. F., & Elphick, M. R. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00145-3 · Cited by 347 · see citing works
Self-citationAnandamide suppresses pain initiation through a peripheral endocannabinoid mechanism
Clapper, J. R., Moreno-Sanz, G., Russo, R., Guijarro, A., Vacondio, F., Duranti, A., Tontini, A., Sanchini, S., Sciolino, N. R., Spradley, J. M., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2632 · Cited by 346 · see citing works
Blockade of Endocannabinoid-Degrading Enzymes Attenuates Neuropathic Pain
Kinsey, S. G., Long, J. Z., O’Neal, S. T., Abdullah, R. A., Poklis, J. L., Boger, D. L., Cravatt, B. F., & Lichtman, A. H. (2009) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.155465 · Cited by 330 · see citing works
Self-citationChemical Probes of Endocannabinoid Metabolism
Blankman, J. L., & Cravatt, B. F. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.006387 · Cited by 327 · see citing works
Self-citationCannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside
Rahn, E. J., & Hohmann, A. G. (2009) · Neurotherapeutics · doi:10.1016/j.nurt.2009.08.002 · Cited by 305 · see citing works
Richardson, D., Pearson, R. G., Kurian, N., Latif, M. L., Garle, M. J., Barrett, D. A., Kendall, D. A., Scammell, B. E., Reeve, A. J., & Chapman, V. (2008) · Arthritis Research & Therapy · doi:10.1186/ar2401 · Cited by 303 · see citing works
Donvito, G., Nass, S. R., Wilkerson, J. L., Curry, Z. A., Schurman, L. D., Kinsey, S. G., & Lichtman, A. H. (2018) · Neuropsychopharmacology · doi:10.1038/npp.2017.204 · Cited by 301 · see citing works
Self-citationLichtman, A. H., Shelton, C. C., Advani, T., & Cravatt, B. F. (2004) · Pain · doi:10.1016/j.pain.2004.01.022 · Cited by 301 · see citing works
Self-citationPatel, S., Roelke, C. T., Rademacher, D. J., & Hillard, C. J. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.03916.x · Cited by 297 · see citing works
Manzanares, J., Julian, M., & Carrascosa, A. (2006) · Current Neuropharmacology · doi:10.2174/157015906778019527 · Cited by 287 · see citing works
FAAH genetic variation enhances fronto-amygdala function in mouse and human
Dincheva, I., Drysdale, A. T., Hartley, C. A., Johnson, D. C., Jing, D., King, E. C., Ra, S., Gray, J. M., Yang, R., DeGruccio, A. M., et al. (2015) · Nature Communications · doi:10.1038/ncomms7395 · Cited by 289 · see citing works
Self-citationActions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models
Jayamanne, A., Greenwood, R., Mitchell, V. A., Aslan, S., Piomelli, D., & Vaughan, C. W. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706510 · Cited by 287 · see citing works
Chiang, K. P. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh216 · Cited by 278 · see citing works
Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling
Azad, S. C., Monory, K., Marsicano, G., Cravatt, B. F., Lutz, B., Zieglgänsberger, W., & Rammes, G. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.2134-04.2004 · Cited by 263 · see citing works
Rademacher, D. J., Meier, S. E., Shi, L., Vanessa Ho, W.-S., Jarrahian, A., & Hillard, C. J. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2007.06.012 · Cited by 233 · see citing works
The endocannabinoid system as a target for novel anxiolytic drugs
Patel, S., Hill, M. N., Cheer, J. F., Wotjak, C. T., & Holmes, A. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.12.033 · Cited by 233 · see citing works
Fegley, D., Kathuria, S., Mercier, R., Li, C., Goutopoulos, A., Makriyannis, A., & Piomelli, D. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400997101 · Cited by 230 · see citing works
Hill, M. N., Kumar, S. A., Filipski, S. B., Iverson, M., Stuhr, K. L., Keith, J. M., Cravatt, B. F., Hillard, C. J., Chattarji, S., & McEwen, B. S. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.90 · Cited by 222 · see citing works
Self-citationEndocannabinoid signaling mediates oxytocin-driven social reward
Wei, D., Lee, D., Cox, C. D., Karsten, C. A., Peñagarikano, O., Geschwind, D. H., Gall, C. M., & Piomelli, D. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1509795112 · Cited by 218 · see citing works
Gorzalka, B. B., Hill, M. N., & Hillard, C. J. (2008) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2008.03.004 · Cited by 211 · see citing works
Cannabis use during adolescent development: Susceptibility to psychiatric illness
Chadwick, B., Miller, M. L., & Hurd, Y. L. (2013) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2013.00129 · Cited by 210 · see citing works
The endogenous cannabinoid system and its role in nociceptive behavior
Cravatt, B. F., & Lichtman, A. H. (2004) · Journal of Neurobiology · doi:10.1002/neu.20080 · Cited by 203 · see citing works
Lynch, M. E., & Ware, M. A. (2015) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-015-9600-6 · Cited by 195 · see citing works
Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality
Naidu, P. S., Varvel, S. A., Ahn, K., Cravatt, B. F., Martin, B. R., & Lichtman, A. H. (2007) · Psychopharmacology · doi:10.1007/s00213-006-0689-4 · Cited by 184 · see citing works
Self-citationGoods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years
Maccarrone, M., Di Marzo, V., Gertsch, J., Grether, U., Howlett, A. C., Hua, T., Makriyannis, A., Piomelli, D., Ueda, N., & van der Stelt, M. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000600 · Cited by 183 · see citing works
Sciolino, N. R., Zhou, W., & Hohmann, A. G. (2011) · Pharmacological Research · doi:10.1016/j.phrs.2011.04.010 · Cited by 179 · see citing works
Moreira, F. A., & Wotjak, C. T. (2009) · Current topics in behavioral neurosciences · doi:10.1007/7854_2009_16 · Cited by 177 · see citing works
A catalytically silent FAAH-1 variant drives anandamide transport in neurons
Fu, J., Bottegoni, G., Sasso, O., Bertorelli, R., Rocchia, W., Masetti, M., Guijarro, A., Lodola, A., Armirotti, A., Garau, G., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.2986 · Cited by 175 · see citing works
Lipids in Psychiatric Disorders and Preventive Medicine
Schneider, M., Levant, B., Reichel, M., Gulbins, E., Kornhuber, J., & Müller, C. P. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.002 · Cited by 175 · see citing works
The <i>N</i>‐Acylethanolamine‐Hydrolyzing Acid Amidase (NAAA)
Tsuboi, K., Takezaki, N., & Ueda, N. (2007) · Chemistry & Biodiversity · doi:10.1002/cbdv.200790159 · Cited by 172 · see citing works
Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase
Kerbrat, A., Ferré, J.-C., Fillatre, P., Ronzière, T., Vannier, S., Carsin-Nicol, B., Lavoué, S., Vérin, M., Gauvrit, J.-Y., Le Tulzo, Y., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1604221 · Cited by 171 · see citing works
TRPV1 in Brain Is Involved in Acetaminophen-Induced Antinociception
Mallet, C., Barrière, D. A., Ermund, A., Jönsson, B. A. G., Eschalier, A., Zygmunt, P. M., & Högestätt, E. D. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012748 · Cited by 165 · see citing works
“TRPV1 and FAAH knockout mice were originally generated by David Julius [24] and Benjamin Cravatt [49].”
MethodPatel, S., Cravatt, B. F., & Hillard, C. J. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300535 · Cited by 164 · see citing works
Self-citationAnalgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain
Jhaveri, M. D., Richardson, D., Kendall, D. A., Barrett, D. A., & Chapman, V. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3326-06.2006 · Cited by 159 · see citing works
Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms
Chang, L., Luo, L., Palmer, J. A., Sutton, S., Wilson, S. J., Barbier, A. J., Breitenbucher, J. G., Chaplan, S. R., & Webb, M. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706699 · Cited by 155 · see citing works
Inhibition of Fatty Acid Binding Proteins Elevates Brain Anandamide Levels and Produces Analgesia
Kaczocha, M., Rebecchi, M. J., Ralph, B. P., Teng, Y.-H. G., Berger, W. T., Galbavy, W., Elmes, M. W., Glaser, S. T., Wang, L., Rizzo, R. C., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0094200 · Cited by 142 · see citing works
“(FAAH), the principal NAE hydrolyzing enzyme in mice [8,9,26].”
BackgroundEndocannabinoids limit excessive mast cell maturation and activation in human skin
Sugawara, K., Bíró, T., Tsuruta, D., Tóth, B. I., Kromminga, A., Zákány, N., Zimmer, A., Funk, W., Gibbs, B. F., Zimmer, A., et al. (2012) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2011.11.009 · Cited by 138 · see citing works
Candidate genes for cannabis use disorders: findings, challenges and directions.
Agrawal, A., & Lynskey, M. T. (2009) · Addiction · doi:10.1111/j.1360-0443.2009.02504.x · Cited by 128 · see citing works
More surprises lying ahead. The endocannabinoids keep us guessing
Piomelli, D. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.07.026 · Cited by 128 · see citing works
Ignatowska‐Jankowska, B. M., Ghosh, S., Crowe, M. S., Kinsey, S. G., Niphakis, M. J., Abdullah, R. A., Tao, Q., O' Neal, S. T., Walentiny, D. M., Wiley, J. L., et al. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12298 · Cited by 128 · see citing works
Self-citationGhosh, S., Wise, L. E., Chen, Y., Gujjar, R., Mahadevan, A., Cravatt, B. F., & Lichtman, A. H. (2013) · Life Sciences · doi:10.1016/j.lfs.2012.06.020 · Cited by 127 · see citing works
Self-citationKinsey, S. G., Long, J. Z., Cravatt, B. F., & Lichtman, A. H. (2010) · The Journal of Pain · doi:10.1016/j.jpain.2010.04.001 · Cited by 118 · see citing works
Self-citationBooker, L., Kinsey, S. G., Abdullah, R. A., Blankman, J. L., Long, J. Z., Ezzili, C., Boger, D. L., Cravatt, B. F., & Lichtman, A. H. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01445.x · Cited by 116 · see citing works
Self-citationEnzymological studies on the biosynthesis of N-acylethanolamines
Ueda, N., Tsuboi, K., & Uyama, T. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.08.010 · Cited by 112 · see citing works
Physical activity and the endocannabinoid system: an overview
Tantimonaco, M., Ceci, R., Sabatini, S., Catani, M. V., Rossi, A., Gasperi, V., & Maccarrone, M. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1575-6 · Cited by 112 · see citing works
Egertová, M., Simon, G. M., Cravatt, B. F., & Elphick, M. R. (2008) · Journal of Comparative Neurology · doi:10.1002/cne.21568 · Cited by 111 · see citing works
Self-citationRegulation of Inflammatory Pain by Inhibition of Fatty Acid Amide Hydrolase
Naidu, P. S., Kinsey, S. G., Guo, T. L., Cravatt, B. F., & Lichtman, A. H. (2010) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.164806 · Cited by 108 · see citing works
Self-citationZhang, D., Saraf, A., Kolasa, T., Bhatia, P., Zheng, G. Z., Patel, M., Lannoye, G. S., Richardson, P., Stewart, A., Rogers, J. C., et al. (2007) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.11.009 · Cited by 99 · see citing works
La Rana, G., Russo, R., Campolongo, P., Bortolato, M., Mangieri, R. A., Cuomo, V., Iacono, A., Raso, G. M., Meli, R., Piomelli, D., et al. (2006) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.100792 · Cited by 97 · see citing works
“Third, genetic deletion or pharmacological inhibition of FAAH ele-vates brain anandamide levels and reduces nocifensive behaviors in mice and rats (Cravatt et al., 2001; Kathuria et al., 2003; Lichtman et al., 2004).”
BackgroundInfluentialGodlewski, G., Alapafuja, S. O., Bátkai, S., Nikas, S. P., Cinar, R., Offertáler, L., Osei-Hyiaman, D., Liu, J., Mukhopadhyay, B., Harvey-White, J., et al. (2010) · Chemistry & Biology · doi:10.1016/j.chembiol.2010.08.013 · Cited by 95 · see citing works
Self-citationEndocannabinoid signaling and the hypothalamic-Pituitary-Adrenal axis
Hillard, C. J., Beatka, M., & Sarvaideo, J. (2016) · Comprehensive physiology · doi:10.1002/cphy.c160005 · Cited by 93 · see citing works
Brusberg, M., Arvidsson, S., Kang, D., Larsson, H., Lindström, E., & Martinez, V. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5166-08.2009 · Cited by 88 · see citing works
Global strategies to integrate the proteome and metabolome
Saghatelian, A., & Cravatt, B. F. (2005) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2004.12.004 · Cited by 85 · see citing works
Self-citationChapter 5 The Endocannabinoid System as A Target for Novel Anxiolytic and Antidepressant Drugs
Gaetani, S., Dipasquale, P., Romano, A., Righetti, L., Cassano, T., Piomelli, D., & Cuomo, V. (2009) · International Review of Neurobiology · doi:10.1016/s0074-7742(09)85005-8 · Cited by 83 · see citing works
Alger, B. E. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2011.220855 · Cited by 82 · see citing works
Da Fonseca Pacheco, D., Klein, A., De Castro Perez, A., Da Fonseca Pacheco, C. M., De Francischi, J. N., & Duarte, I. D. G. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.175 · Cited by 81 · see citing works
Rossi, S., De Chiara, V., Musella, A., Sacchetti, L., Cantarella, C., Castelli, M., Cavasinni, F., Motta, C., Studer, V., Bernardi, G., et al. (2010) · Molecular Pharmacology · doi:10.1124/mol.110.064196 · Cited by 82 · see citing works
Self-citationBoileau, I., Mansouri, E., Williams, B., Le Foll, B., Rusjan, P., Mizrahi, R., Tyndale, R. F., Huestis, M. A., Payer, D. E., Wilson, A. A., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.04.012 · Cited by 82 · see citing works
Wilkerson, J. L., Ghosh, S., Mustafa, M., Abdullah, R. A., Niphakis, M. J., Cabrera, R., Maldonado, R. L., Cravatt, B. F., & Lichtman, A. H. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.11.015 · Cited by 78 · see citing works
Self-citationNadal, X., La Porta, C., Andreea Bura, S., & Maldonado, R. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.01.077 · Cited by 76 · see citing works
Karbarz, M. J., Luo, L., Chang, L., Tham, C.-S., Palmer, J. A., Wilson, S. J., Wennerholm, M. L., Brown, S. M., Scott, B. P., Apodaca, R. L., et al. (2009) · Anesthesia & Analgesia · doi:10.1213/ane.0b013e31818c7cbd · Cited by 74 · see citing works
Cassano, T., Gaetani, S., Macheda, T., Laconca, L., Romano, A., Morgese, M. G., Cimmino, C. S., Chiarotti, F., Bambico, F. R., Gobbi, G., et al. (2011) · Psychopharmacology · doi:10.1007/s00213-010-2051-0 · Cited by 72 · see citing works
Kawahara, H., Drew, G., Christie, M., & Vaughan, C. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01157.x · Cited by 67 · see citing works
Wallace, V. C. J., Segerdahl, A. R., Lambert, D. M., Vandevoorde, S., Blackbeard, J., Pheby, T., Hasnie, F., & Rice, A. S. C. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707326 · Cited by 66 · see citing works
Malek, N., Mrugala, M., Makuch, W., Kolosowska, N., Przewlocka, B., Binkowski, M., Czaja, M., Morera, E., Di Marzo, V., & Starowicz, K. (2015) · Pain · doi:10.1097/j.pain.0000000000000132 · Cited by 63 · see citing works
Desroches, J., Guindon, J., Lambert, C., & Beaulieu, P. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.322 · Cited by 63 · see citing works
Barrière, D. A., Mallet, C., Blomgren, A., Simonsen, C., Daulhac, L., Libert, F., Chapuy, E., Etienne, M., Högestätt, E. D., Zygmunt, P. M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070690 · Cited by 62 · see citing works
Ghosh, S., Kinsey, S. G., Liu, Q.-S., Hruba, L., McMahon, L. R., Grim, T. W., Merritt, C. R., Wise, L. E., Abdullah, R. A., Selley, D. E., et al. (2015) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.115.222851 · Cited by 54 · see citing works
Self-citationNovel inhibitors of fatty acid amide hydrolase
Sit, S. Y., Conway, C., Bertekap, R., Xie, K., Bourin, C., Burris, K., & Deng, H. (2007) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2007.04.009 · Cited by 52 · see citing works
Grim, T. W., Ghosh, S., Hsu, K.-L., Cravatt, B. F., Kinsey, S. G., & Lichtman, A. H. (2014) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2014.07.008 · Cited by 50 · see citing works
Self-citationToward Atomistic Modeling of Irreversible Covalent Inhibitor Binding Kinetics
Yu, H. S., Gao, C., Lupyan, D., Wu, Y., Kimura, T., Wu, C., Jacobson, L., Harder, E., Abel, R., & Wang, L. (2019) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.9b00268 · Cited by 39 · see citing works
Nozaki, C., Markert, A., & Zimmer, A. (2015) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2015.04.001 · Cited by 45 · see citing works
Schlosburg, J. E., Kinsey, S. G., Ignatowska-Jankowska, B., Ramesh, D., Abdullah, R. A., Tao, Q., Booker, L., Long, J. Z., Selley, D. E., Cravatt, B. F., et al. (2014) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.212753 · Cited by 44 · see citing works
Self-citationMiller, L. L., Picker, M. J., Umberger, M. D., Schmidt, K. T., & Dykstra, L. A. (2012) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.191478 · Cited by 44 · see citing works
Differential effects of endocannabinoid catabolic inhibitors on morphine withdrawal in mice
Gamage, T. F., Ignatowska-Jankowska, B. M., Muldoon, P. P., Cravatt, B. F., Damaj, M. I., & Lichtman, A. H. (2015) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2014.11.015 · Cited by 40 · see citing works
Self-citationEffects of COX-2 inhibition on spinal nociception: the role of endocannabinoids.
Staniaszek, L., Norris, L., Kendall, D., Barrett, D., & Chapman, V (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00703.x · Cited by 36 · see citing works
Supra-spinal FAAH is required for the analgesic action of paracetamol in an inflammatory context
Dalmann, R., Daulhac, L., Antri, M., Eschalier, A., & Mallet, C. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.11.006 · Cited by 32 · see citing works
Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms
Sirrs, S., van Karnebeek, C. D., Peng, X., Shyr, C., Tarailo-Graovac, M., Mandal, R., Testa, D., Dubin, D., Carbonetti, G., Glynn, S. E., et al. (2015) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-015-0248-3 · Cited by 28 · see citing works
Ex Vivo Imaging of Fatty Acid Amide Hydrolase Activity and Its Inhibition in the Mouse Brain
Glaser, S. T., Gatley, S. J., & Gifford, A. N. (2006) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.094748 · Cited by 26 · see citing works
p21-activated kinase 1 restricts tonic endocannabinoid signaling in the hippocampus
Xia, S., Zhou, Z., Leung, C., Zhu, Y., Pan, X., Qi, J., Morena, M., Hill, M. N., Xie, W., & Jia, Z. (2016) · eLife · doi:10.7554/elife.14653 · Cited by 21 · see citing works
- 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 › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review