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Research ArticleAccelerated Communication

Monoacylglycerol Lipase Activity Is a Critical Modulator of the Tone and Integrity of the Endocannabinoid System

Pranab K. Chanda, Ying Gao, Lilly Mark, Joan Btesh, Brian W. Strassle, Peimin Lu, Michael J. Piesla, Mei-Yi Zhang, Brendan Bingham, Albert Uveges, Dianne Kowal, David Garbe, Evguenia V. Kouranova, Robert H. Ring, Brian Bates, Menelas N. Pangalos, Jeffrey D. Kennedy, Garth T. Whiteside and Tarek A. Samad
Molecular Pharmacology December 2010, 78 (6) 996-1003; DOI: https://doi.org/10.1124/mol.110.068304
Pranab K. Chanda
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Ying Gao
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Lilly Mark
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Joan Btesh
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Brian W. Strassle
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Peimin Lu
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Michael J. Piesla
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Mei-Yi Zhang
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Brendan Bingham
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Albert Uveges
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Dianne Kowal
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David Garbe
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Evguenia V. Kouranova
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Robert H. Ring
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Brian Bates
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Menelas N. Pangalos
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Jeffrey D. Kennedy
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Garth T. Whiteside
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Tarek A. Samad
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Abstract

Endocannabinoids are lipid molecules that serve as natural ligands for the cannabinoid receptors CB1 and CB2. They modulate a diverse set of physiological processes such as pain, cognition, appetite, and emotional states, and their levels and functions are tightly regulated by enzymatic biosynthesis and degradation. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid in the brain and is believed to be hydrolyzed primarily by the serine hydrolase monoacylglycerol lipase (MAGL). Although 2-AG binds and activates cannabinoid receptors in vitro, when administered in vivo, it induces only transient cannabimimetic effects as a result of its rapid catabolism. Here we show using a mouse model with a targeted disruption of the MAGL gene that MAGL is the major modulator of 2-AG hydrolysis in vivo. Mice lacking MAGL exhibit dramatically reduced 2-AG hydrolase activity and highly elevated 2-AG levels in the nervous system. A lack of MAGL activity and subsequent long-term elevation of 2-AG levels lead to desensitization of brain CB1 receptors with a significant reduction of cannabimimetic effects of CB1 agonists. Also consistent with CB1 desensitization, MAGL-deficient mice do not show alterations in neuropathic and inflammatory pain sensitivity. These findings provide the first genetic in vivo evidence that MAGL is the major regulator of 2-AG levels and signaling and reveal a pivotal role for 2-AG in modulating CB1 receptor sensitization and endocannabinoid tone.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.068304.

  • ABBREVIATIONS:

    CB
    cannabinoid
    2-AG
    2-arachidonoylglycerol
    FAAH
    fatty acid amide hydrolase
    MAGL
    monoacylglycerol lipase
    CFA
    complete Freund's adjuvant
    SNL
    spinal nerve ligation
    ANOVA
    analysis of variance
    CNS
    central nervous system
    ARA
    anandamide
    LC/MS/MS
    liquid chromatography-tandem mass spectrometry
    AA
    arachidonic acid
    SR141716
    rimonabant
    JZL184
    4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate
    WIN55212
    (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone
    CP55940
    5-(1,1-dimethylheptyl)-2-(5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)phenol.

  • Received August 20, 2010.
  • Accepted September 14, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (6)
Molecular Pharmacology
Vol. 78, Issue 6
1 Dec 2010
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Research ArticleAccelerated Communication

Monoacylglycerol Lipase Activity Is a Critical Modulator of the Tone and Integrity of the Endocannabinoid System

Pranab K. Chanda, Ying Gao, Lilly Mark, Joan Btesh, Brian W. Strassle, Peimin Lu, Michael J. Piesla, Mei-Yi Zhang, Brendan Bingham, Albert Uveges, Dianne Kowal, David Garbe, Evguenia V. Kouranova, Robert H. Ring, Brian Bates, Menelas N. Pangalos, Jeffrey D. Kennedy, Garth T. Whiteside and Tarek A. Samad
Molecular Pharmacology December 1, 2010, 78 (6) 996-1003; DOI: https://doi.org/10.1124/mol.110.068304

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Research ArticleAccelerated Communication

Monoacylglycerol Lipase Activity Is a Critical Modulator of the Tone and Integrity of the Endocannabinoid System

Pranab K. Chanda, Ying Gao, Lilly Mark, Joan Btesh, Brian W. Strassle, Peimin Lu, Michael J. Piesla, Mei-Yi Zhang, Brendan Bingham, Albert Uveges, Dianne Kowal, David Garbe, Evguenia V. Kouranova, Robert H. Ring, Brian Bates, Menelas N. Pangalos, Jeffrey D. Kennedy, Garth T. Whiteside and Tarek A. Samad
Molecular Pharmacology December 1, 2010, 78 (6) 996-1003; DOI: https://doi.org/10.1124/mol.110.068304
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