Activation of the endocannabinoid system by organophosphorus nerve agents

Nat Chem Biol. 2008 Jun;4(6):373-8. doi: 10.1038/nchembio.86. Epub 2008 Apr 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Animals
  • Arachidonic Acid / analysis
  • Arachidonic Acids / analysis
  • Brain / drug effects
  • Brain / enzymology
  • Brain / metabolism
  • Cannabinoid Receptor Modulators / antagonists & inhibitors
  • Cannabinoid Receptor Modulators / chemistry
  • Cannabinoid Receptor Modulators / metabolism*
  • Endocannabinoids*
  • Female
  • Glycerides / analysis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Conformation
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Organophosphorus Compounds / chemistry
  • Organophosphorus Compounds / pharmacology*
  • Polyunsaturated Alkamides / analysis
  • Receptor, Cannabinoid, CB1 / agonists*
  • Receptor, Cannabinoid, CB1 / drug effects
  • Receptors, Cannabinoid / drug effects
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Stereoisomerism

Substances

  • 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

Associated data

  • PubChem-Substance/49681165
  • PubChem-Substance/49681166
  • PubChem-Substance/49681167
  • PubChem-Substance/49681168
  • PubChem-Substance/49681169
  • PubChem-Substance/49681170
  • PubChem-Substance/49681171
  • PubChem-Substance/49681172
  • PubChem-Substance/49681173
  • PubChem-Substance/49681174
  • PubChem-Substance/49681175
  • PubChem-Substance/49681176
  • PubChem-Substance/49681177
  • PubChem-Substance/49681178
  • PubChem-Substance/49681179
  • PubChem-Substance/49681180
  • PubChem-Substance/49681181
  • PubChem-Substance/49681182
  • PubChem-Substance/49681183
  • PubChem-Substance/49681184
  • PubChem-Substance/49681185
  • PubChem-Substance/49681186
  • PubChem-Substance/49681187
  • PubChem-Substance/49681188
  • PubChem-Substance/49681189
  • PubChem-Substance/49681190
  • PubChem-Substance/49681191
  • PubChem-Substance/49681192
  • PubChem-Substance/49681193
  • PubChem-Substance/49681194
  • PubChem-Substance/49681195
  • PubChem-Substance/49681196
  • PubChem-Substance/49681197
  • PubChem-Substance/49681198