Prolonged monoacylglycerol lipase blockade causes equivalent cannabinoid receptor type 1 receptor-mediated adaptations in fatty acid amide hydrolase wild-type and knockout mice
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Complementary genetic and pharmacological approaches to inhibit monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), the primary hydrolytic enzymes of the respective endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine, enable the exploration of potential therapeutic applications and physiologic roles of these enzymes. Complete and simultaneous inhibition of both FAAH and MAGL produces greatly enhanced cannabimimetic responses, including increased antinociception, and other cannabimimetic effects, far beyond those seen with inhibition of either enzyme alone. While cannabinoid receptor type 1 (CB1) function is maintained following chronic FAAH inactivation, prolonged excessive elevation of brain 2-AG levels, via MAGL inhibition, elicits both behavioral and molecular signs of cannabinoid tolerance and dependence. Here, we evaluated the consequences of a high dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate; 40 mg/kg] given acutely or for 6 days in FAAH(-/-) and (+/+) mice. While acute administration of JZL184 to FAAH(-/-) mice enhanced the magnitude of a subset of cannabimimetic responses, repeated JZL184 treatment led to tolerance to its antinociceptive effects, cross-tolerance to the pharmacological effects of Δ(9)-tetrahydrocannabinol, decreases in CB1 receptor agonist-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate binding, and dependence as indicated by rimonabant-precipitated withdrawal behaviors, regardless of genotype. Together, these data suggest that simultaneous elevation of both endocannabinoids elicits enhanced cannabimimetic activity but MAGL inhibition drives CB1 receptor functional tolerance and cannabinoid dependence.
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Chronic high-dose MAGL inhibition desensitizes CB1R and produces a phenotype more akin to CB1R antagonism than agonism.
“the ability of chronic, high-dose MAGL inhibition to desensitize the CB1R and produce a phenotype that is more akin to CB1R antagonism than agonism (Schlosburg et al., 2010; Schlosburg et al., 2014).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Schlosburg et al., 2014
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Cites
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
2-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
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-citationBrain 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
Cravatt, B. F., Demarest, K., Patricelli, M. P., Bracey, M. H., Giang, D. K., Martin, B. R., & Lichtman, A. H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.161191698 · Cited by 1,310 · see citing works
Self-citationModulation 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
The endocannabinoid system and the brain.
Mechoulam, R., & Parker, L. A. (2013) · Annual Review of Psychology · doi:10.1146/annurev-psych-113011-143739 · Cited by 1,090 · see citing works
Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects
Long, J. Z., Li, W., Booker, L., Burston, J. J., Kinsey, S. G., Schlosburg, J. E., Pavón, F. J., Serrano, A., Selley, D. E., Parsons, L. H., et al. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.129 · Cited by 938 · see citing works
Self-citationTargeting the endocannabinoid system: to enhance or reduce?
Marzo, V. D. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2553 · Cited by 798 · see citing works
Chronic 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-citationThe serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors
Marrs, W., Blankman, J. L., Horne, E. A., Thomazeau, A., Lin, Y. H., Coy, J. W., Bodor, Á. L., Muccioli, G. G., Hu, S. S., Woodruff, G., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2601 · Cited by 442 · 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-citationModulating the endocannabinoid system in human health and disease – successes and failures
Pacher, P., & Kunos, G. (2013) · FEBS Journal · doi:10.1111/febs.12260 · Cited by 406 · see citing works
Long, J. Z., Nomura, D. K., Vann, R. E., Walentiny, D. M., Booker, L., Jin, X., Burston, J. J., Sim‐Selley, L. J., Lichtman, A. H., Wiley, J. L., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909411106 · Cited by 393 · see citing works
Self-citationPatel, S., & Hillard, C. J. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.101287 · Cited by 390 · see citing works
Gonsiorek, W., Lunn, C. A., Fan, X., Narula, S. K., Lundell, D. J., & Hipkin, R. W. (2000) · Molecular Pharmacology · doi:10.1016/s0026-895x(24)26516-0 · Cited by 370 · see citing works
Mackie, K., Devane, W. A., & Hille, B. (1993) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)13215-x · Cited by 365 · 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-citationEvidence That the Cannabinoid CB1 Receptor Is a 2-Arachidonoylglycerol Receptor
Sugiura, T., Kodaka, T., Nakane, S., Miyashita, T., Kondo, S., Suhara, Y., Takayama, H., Waku, K., Seki, C., Baba, N., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.5.2794 · Cited by 311 · see citing works
Long, J. Z., Nomura, D. K., & Cravatt, B. F. (2009) · Chemistry & Biology · doi:10.1016/j.chembiol.2009.05.009 · Cited by 305 · see citing works
Self-citationAnandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum
Maccarrone, M., Rossi, S., Bari, M., Chiara, V. D., Fezza, F., Musella, A., Gasperi, V., Prosperetti, C., Bernardi, G., Finazzi‐Agrò, A., et al. (2008) · Nature Neuroscience · doi:10.1038/nn2042 · Cited by 293 · see citing works
Self-citationMaione, S., Bisogno, T., de Novellis, V., Palazzo, E., Cristino, L., Valenti, M., Petrosino, S., Guglielmotti, V., Rossi, F., & Marzo, V. D. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.093286 · Cited by 293 · see citing works
Taschler, U., Radner, F. P. W., Heier, C., Schreiber, R., Schweiger, M., Schoiswohl, G., Preiss-Landl, K., Jaeger, D., Reiter, B., Köfeler, H. C., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.215434 · Cited by 284 · see citing works
Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like responses
Busquets-Garcia, A., Puighermanal, E., Pastor, A., de la Torre, R., Maldonado, R., & Ozaita, A. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.04.022 · Cited by 273 · see citing works
Hillard, C. J. (2000) · Prostaglandins & Other Lipid Mediators · doi:10.1016/s0090-6980(00)00051-4 · Cited by 255 · see citing works
Chanda, P. K., Gao, Y., Mark, L., Btesh, J., Strassle, B. W., Lu, P., Piesla, M. J., Zhang, M.-Y., Bingham, B., Uveges, A. J., et al. (2010) · Molecular Pharmacology · doi:10.1124/mol.110.068304 · Cited by 228 · see citing works
Alhouayek, M., Lambert, D. M., Delzenne, N. M., Cani, P. D., & Muccioli, G. G. (2011) · The FASEB Journal · doi:10.1096/fj.10-176602 · Cited by 208 · see citing works
Dinis, P., Charrua, A., Avelino, A., Yaqoob, M., Bevan, S., Nagy, I., & Cruz, F. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2657-04.2004 · Cited by 205 · see citing works
Chang, J. W., Niphakis, M. J., Lum, K. M., Cognetta, A. B., Wang, C., Matthews, M. L., Niessen, S., Buczynski, M. W., Parsons, L. H., & Cravatt, B. F. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.03.009 · Cited by 193 · see citing works
Self-citationBlankman, J. L., Long, J. Z., Trauger, S. A., Siuzdak, G. E., & Cravatt, B. F. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217121110 · Cited by 193 · see citing works
Self-citationSciolino, N. R., Zhou, W., & Hohmann, A. G. (2011) · Pharmacological Research · doi:10.1016/j.phrs.2011.04.010 · Cited by 179 · see citing works
Kinsey, S. G., Wise, L. E., Ramesh, D., Abdullah, R., Selley, D. E., Cravatt, B. F., & Lichtman, A. H. (2013) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.201426 · Cited by 169 · see citing works
Self-citationGuindon, J., Lai, Y., Takacs, S. M., Bradshaw, H. B., & Hohmann, A. G. (2013) · Pharmacological Research · doi:10.1016/j.phrs.2012.10.013 · Cited by 160 · see citing works
Savinainen, J. R., Järvinen, T., Laine, K., & Laitinen, J. T. (2001) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704297 · Cited by 159 · see citing works
Pan, B., Wang, W., Zhong, P., Blankman, J. L., Cravatt, B. F., & Liu, Q.-S. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2075-11.2011 · Cited by 147 · see citing works
Self-citationIgnatowska‐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-citationSim‐Selley, L. J., & Martin, B. R. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.035618 · Cited by 125 · see citing works
Guindon, J., Guijarro, A. I., Piomelli, D., & Hohmann, A. G. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01192.x · Cited by 120 · see citing works
Kinsey, 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-citationWu, D., Yang, L., Goschke, A., Stumm, R. K., Brandenburg, L., Liang, Y.-J., Höllt, V., & Koch, T. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05063.x · Cited by 107 · see citing works
Solinas, M., Tanda, G., Justinová, Z., Wertheim, C. E., Yaşar, S., Piomelli, D., Vadivel, S. K., Makriyannis, A., & Goldberg, S. R. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.114124 · Cited by 104 · see citing works
Luk, T., Jin, W., Zvonok, A. M., Lu, D., Lin, X., Chavkin, C., Makriyannis, A., & Mackie, K. (2004) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705792 · Cited by 99 · see citing works
Hsu, K., Tsuboi, K., Chang, J. W., Whitby, L. R., Speers, A. E., Pugh, H. M., & Cravatt, B. F. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400899c · Cited by 84 · see citing works
Self-citationFalenski, K. W., Thorpe, A. J., Schlosburg, J. E., Cravatt, B. F., Abdullah, R. A., Smith, T. H., Selley, D. E., Lichtman, A. H., & Sim‐Selley, L. J. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.44 · Cited by 83 · see citing works
Self-citationKhasabova, I. A., Chandiramani, A., Harding-Rose, C., Simone, D. A., & Seybold, V. S. (2011) · Pharmacological Research · doi:10.1016/j.phrs.2011.03.007 · Cited by 75 · see citing works
The role of TRPV1 receptors in the antinociceptive effect of anandamide at spinal level
Horváth, G., Kékesi, G., Nagy, E., & Benedek, G. (2007) · Pain · doi:10.1016/j.pain.2007.04.032 · Cited by 74 · see citing works
Ramesh, D., Gamage, T. F., Vanuytsel, T., Owens, R. A., Abdullah, R. A., Niphakis, M. J., Shea‐Donohue, T., Cravatt, B. F., & Lichtman, A. H. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2012.269 · Cited by 70 · see citing works
Self-citationActions of the dual FAAH/MAGL inhibitor JZL195 in a murine inflammatory pain model
Anderson, W. B., Gould, M. J., Torres, R. D., Mitchell, V. A., & Vaughan, C. W. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.12.018 · Cited by 67 · see citing works
Wise, L. E., Long, K. A., Abdullah, R. A., Long, J. Z., Cravatt, B. F., & Lichtman, A. H. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn200130s · Cited by 64 · see citing works
Self-citationParker, L. A., Limebeer, C. L., Rock, E. M., Litt, D., Kwiatkowska, M., & Piomelli, D. (2009) · Physiology & Behavior · doi:10.1016/j.physbeh.2009.02.014 · Cited by 62 · see citing works
Sticht, M. A., Long, J. Z., Rock, E. M., Limebeer, C. L., Mechoulam, R., Cravatt, B. F., & Parker, L. A. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01407.x · Cited by 54 · see citing works
Self-citationRubino, T., Viganò, D., Costa, B., Colleoni, M., & Parolaro, D. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0752478.x · Cited by 46 · see citing works
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- Ignatowska-Jankowska BM, Ghosh S, Crowe MS, Kinsey SG, Niphakis MJ, Abdullah RA, Tao Q, O' Neal ST, Walentiny DM, and Wiley JL, et al. (2014) In vivo char- acterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects. Br J Pharmacol 171: 1392-1407.
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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
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- Authors
- 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., & Lichtman, A. H.
- Affiliations
- West Virginia University (US)
- ORCID
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 350
- Issue
- 2
- Pages
- 196-204
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC4109488
- OpenAlex
- W1986509856
- Cited by
- 44
- References
- 55
- Citations by year
- 2026: 1 · 2025: 4 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 2 · 2019: 1 · 2018: 6 · 2017: 7 · 2015: 4 · 2014: 3
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (F31DA026279, P01DA009789, R01DA015197, R01DA032933, P30DA033934, F31DA028333, P01DA017259, T32DA007027)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- monoacylglycerol lipase, fatty acid amide hydrolase, cannabinoid receptor type 1, 2-arachidonoylglycerol, JZL184, endocannabinoid system, cannabinoid tolerance, antinociception, cross-tolerance, tetrahydrocannabinol
- MeSH terms
- Fatty Acid Amide Hydrolases, Adaptation, Physiological, Amidohydrolases, Animals, Male, Mice, Inbred C57BL, Monoacylglycerol Lipases, Piperidines, Dronabinol, Mice, Knockout, Receptor, Cannabinoid, CB1, Mice, Benzodioxoles, Endocannabinoids
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