Home LiteratureArticle Details
PMID: 18438404 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Activation of the endocannabinoid system by organophosphorus nerve agents.

Nature chemical biology ·Vol. 4 ·No. 6 ·2008-06-00 ·Pages 373-8

Nomura DK, Blankman JL, Simon GM, Fujioka K, Issa RS, Ward AM, Cravatt BF, Casida JE

Abstract

Delta(9)-tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana, has useful medicinal properties but also undesirable side effects. The brain receptor for THC, CB(1), is also activated by the endogenous cannabinoids anandamide and 2-arachidonylglycerol (2-AG). Augmentation of endocannabinoid signaling by blockade of their metabolism may offer a more selective pharmacological approach compared with CB(1) agonists. Consistent with this premise, inhibitors of the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH) produce analgesic and anxiolytic effects without cognitive defects. In contrast, we show that dual blockade of the endocannabinoid-degrading enzymes monoacylglycerol lipase (MAGL) and FAAH by selected organophosphorus agents leads to greater than ten-fold elevations in brain levels of both 2-AG and anandamide and to robust CB(1)-dependent behavioral effects that mirror those observed with CB(1) agonists. Arachidonic acid levels are decreased by the organophosphorus agents in amounts equivalent to elevations in 2-AG, which indicates that endocannabinoid and eicosanoid signaling pathways may be coordinately regulated in the brain.

MeSH Terms
Amidohydrolases/antagonists & inhibitors Animals Arachidonic Acid/analysis Arachidonic Acids/analysis Brain/drug effects,enzymology,metabolism Cannabinoid Receptor Modulators/antagonists & inhibitors,chemistry,metabolism Endocannabinoids Female Glycerides/analysis Male Mice Mice, Inbred C57BL Mice, Knockout Molecular Conformation Monoacylglycerol Lipases/antagonists & inhibitors Organophosphorus Compounds/chemistry,pharmacology Polyunsaturated Alkamides/analysis Receptor, Cannabinoid, CB1/agonists,drug effects Receptors, Cannabinoid/drug effects Signal Transduction/drug effects,physiology Stereoisomerism
Chemicals
Arachidonic Acids Cannabinoid Receptor Modulators Endocannabinoids Glycerides Organophosphorus Compounds Polyunsaturated Alkamides Receptor, Cannabinoid, CB1 Receptors, Cannabinoid Arachidonic Acid glyceryl 2-arachidonate Monoacylglycerol Lipases Amidohydrolases fatty-acid amide hydrolase anandamide
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Nomura Daniel K
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, 114 Wellman Hall, Berkeley, California 94720-3112, USA.
Blankman Jacqueline L
Simon Gabriel M
Fujioka Kazutoshi
Issa Roger S
Ward Anna M
Cravatt Benjamin F
Casida John E
References (41)
41 references, click to expand
  1. Mechanism-based profiling of enzyme families.
    Chem Rev. 2006 Aug;106(8):3279-301 PMID: 16895328
  2. An optimized approach to study endocannabinoid signaling: evidence against constitutive activity of rat brain adenosine A1 and cannabinoid CB1 receptors.
    Br J Pharmacol. 2003 Dec;140(8):1451-9 PMID: 14623770
  3. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.
    Chem Biol. 2007 Dec;14(12):1347-56 PMID: 18096503
  4. RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol.
    Mol Pharmacol. 2004 Nov;66(5):1260-4 PMID: 15272052
  5. The endocannabinoid system in targeting inflammatory neurodegenerative diseases.
    Trends Pharmacol Sci. 2007 Apr;28(4):180-7 PMID: 17350694
  6. Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity.
    Nat Genet. 2003 Apr;33(4):477-85 PMID: 12640454
  7. Isolation and structure of a brain constituent that binds to the cannabinoid receptor.
    Science. 1992 Dec 18;258(5090):1946-9 PMID: 1470919
  8. Monoacylglycerol lipase inhibition by organophosphorus compounds leads to elevation of brain 2-arachidonoylglycerol and the associated hypomotility in mice.
    Toxicol Appl Pharmacol. 2006 Feb 15;211(1):78-83 PMID: 16310817
  9. Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis.
    J Biol Chem. 2002 Feb 15;277(7):4806-15 PMID: 11717312
  10. Catabolism of intracellular N-terminal acetylated proteins: involvement of acylpeptide hydrolase and acylase.
    Biochimie. 2005 Aug;87(8):673-85 PMID: 15927344
  11. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain.
    Biochem Biophys Res Commun. 1995 Oct 4;215(1):89-97 PMID: 7575630
  12. A streamlined platform for high-content functional proteomics of primary human specimens.
    Nat Methods. 2005 Sep;2(9):691-7 PMID: 16118640
  13. Profiling serine hydrolase activities in complex proteomes.
    Biochemistry. 2001 Apr 3;40(13):4005-15 PMID: 11300781
  14. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice.
    Proc Natl Acad Sci U S A. 1999 May 11;96(10):5780-5 PMID: 10318961
  15. Subacute neurotoxicity induced in mice by potent organophosphorus neuropathy target esterase inhibitors.
    Toxicol Appl Pharmacol. 1996 Jul;139(1):195-202 PMID: 8685903
  16. Cannabinoid properties of methylfluorophosphonate analogs.
    J Pharmacol Exp Ther. 2000 Sep;294(3):1209-18 PMID: 10945879
  17. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase.
    Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9371-6 PMID: 11470906
  18. Dual roles of brain serine hydrolase KIAA1363 in ether lipid metabolism and organophosphate detoxification.
    Toxicol Appl Pharmacol. 2008 Apr 1;228(1):42-8 PMID: 18164358
  19. An endocannabinoid mechanism for stress-induced analgesia.
    Nature. 2005 Jun 23;435(7045):1108-12 PMID: 15973410
  20. Endocannabinoids and related compounds: walking back and forth between plant natural products and animal physiology.
    Chem Biol. 2007 Jul;14(7):741-56 PMID: 17656311
  21. Therapeutic potential of endocannabinoid-hydrolysing enzyme inhibitors.
    Basic Clin Pharmacol Toxicol. 2007 Nov;101(5):287-93 PMID: 17910610
  22. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin.
    Br J Pharmacol. 2008 Jan;153(2):199-215 PMID: 17828291
  23. Discovering potent and selective reversible inhibitors of enzymes in complex proteomes.
    Nat Biotechnol. 2003 Jun;21(6):687-91 PMID: 12740587
  24. Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity.
    Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):787-92 PMID: 10639158
  25. Fatty acid amide hydrolase inhibition by neurotoxic organophosphorus pesticides.
    Toxicol Appl Pharmacol. 2001 May 15;173(1):48-55 PMID: 11350214
  26. Structure and function of fatty acid amide hydrolase.
    Annu Rev Biochem. 2005;74:411-32 PMID: 15952893
  27. Activity-based protein profiling for the functional annotation of enzymes.
    Nat Methods. 2007 Oct;4(10):822-7 PMID: 17901872
  28. Evidence that mouse brain neuropathy target esterase is a lysophospholipase.
    Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7983-7 PMID: 12805562
  29. Ethyl octylphosphonofluoridate and analogs: optimized inhibitors of neuropathy target esterase.
    Chem Res Toxicol. 1995 Dec;8(8):1070-5 PMID: 8605290
  30. Brain lipid metabolism in the cPLA2 knockout mouse.
    J Lipid Res. 2003 Jan;44(1):109-17 PMID: 12518029
  31. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors.
    Nat Neurosci. 2007 Jul;10(7):870-9 PMID: 17558404
  32. Brain monoglyceride lipase participating in endocannabinoid inactivation.
    Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10819-24 PMID: 12136125
  33. Endocannabinoids and the regulation of their levels in health and disease.
    Curr Opin Lipidol. 2007 Apr;18(2):129-40 PMID: 17353660
  34. The endocannabinoid system controls key epileptogenic circuits in the hippocampus.
    Neuron. 2006 Aug 17;51(4):455-66 PMID: 16908411
  35. Extracellular metabolism of pulmonary surfactant: the role of a new serine protease.
    Annu Rev Physiol. 1995;57:135-50 PMID: 7778861
  36. A functional proteomic strategy to discover inhibitors for uncharacterized hydrolases.
    J Am Chem Soc. 2007 Aug 8;129(31):9594-5 PMID: 17629278
  37. An enzyme that regulates ether lipid signaling pathways in cancer annotated by multidimensional profiling.
    Chem Biol. 2006 Oct;13(10):1041-50 PMID: 17052608
  38. Inverse agonism and neutral antagonism at cannabinoid CB1 receptors.
    Life Sci. 2005 Feb 4;76(12):1307-24 PMID: 15670612
  39. Organophosphate toxicology: safety aspects of nonacetylcholinesterase secondary targets.
    Chem Res Toxicol. 2004 Aug;17(8):983-98 PMID: 15310231
  40. A brain detoxifying enzyme for organophosphorus nerve poisons.
    Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6195-200 PMID: 15840715
  41. Endogenous cannabinoids in the brain and peripheral tissues: regulation of their levels and control of food intake.
    Int J Obes (Lond). 2006 Apr;30 Suppl 1:S7-S12 PMID: 16570107
Article Info
Journal
Nature chemical biology
Abbr.
Nat Chem Biol
ISSN
1552-4469
DOI
10.1038/nchembio.86
Published
2008-06-00
Epub
2008-00-27
Pages
373-8
Language
English
Region
United States
NLM ID
101231976
PMCID
PMC2597283
Subset
IM
Grants
NCI NIH HHS · CA087660 · United States
NCI NIH HHS · R37 CA087660 · United States
NIEHS NIH HHS · R01 ES008762-09 · United States
NIEHS NIH HHS · ES008762 · United States
NCI NIH HHS · R01 CA087660-08 · United States
NIEHS NIH HHS · R01 ES008762 · United States
NCI NIH HHS · R01 CA087660 · United States
Databases
PubChem-Substance
49681165, 49681166, 49681167, 49681168, 49681169, 49681170, 49681171, 49681172, 49681173, 49681174, 49681175, 49681176, 49681177, 49681178, 49681179, 49681180, 49681181, 49681182, 49681183, 49681184, 49681185, 49681186, 49681187, 49681188, 49681189, 49681190, 49681191, 49681192, 49681193, 49681194, 49681195, 49681196, 49681197, 49681198
External Links
PubMed source DOI: 10.1038/nchembio.86 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2