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Activation of the endocannabinoid system by organophosphorus nerve agents

Academic Article
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Overview

related to degree

  • Blankman, Jacqueline, Ph.D. in Chemistry, Scripps Research 2006 - 2012
  • Simon, Gabriel, Ph.D. in Chemistry, Scripps Research 2004 - 2009

authors

  • Nomura, D. K.
  • Blankman, Jacqueline
  • Simon, Gabriel
  • Fujioka, K.
  • Issa, R. S.
  • Ward, A. M.
  • Cravatt, Benjamin
  • Casida, J. E.

publication date

  • June 2008

journal

  • Nature Chemical Biology  Journal

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.

subject areas

  • Amidohydrolases
  • Animals
  • Arachidonic Acid
  • Arachidonic Acids
  • Brain
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Female
  • Glycerides
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Conformation
  • Monoacylglycerol Lipases
  • Organophosphorus Compounds
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1
  • Receptors, Cannabinoid
  • Signal Transduction
  • Stereoisomerism
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Identity

PubMed Central ID

  • PMC2597283

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.86

PubMed ID

  • 18438404
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Additional Document Info

start page

  • 373

end page

  • 378

volume

  • 4

issue

  • 6

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