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Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo

Academic Article
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Overview

authors

  • Lichtman, A. H.
  • Hawkins, E. G.
  • Griffin, G.
  • Cravatt, Benjamin

publication date

  • 2002

journal

  • Journal of Pharmacology and Experimental Therapeutics  Journal

abstract

  • Fatty acid amides (FAAs) represent a class of neuromodulatory lipids that includes the endocannabinoid anandamide and the sleep-inducing substance oleamide. Both anandamide and oleamide produce behavioral effects indicative of cannabinoid activity, but only anandamide binds the cannabinoid (CB1) receptor in vitro. Accordingly, oleamide has been proposed to induce its behavioral effects by serving as a competitive substrate for the brain enzyme fatty acid amide hydrolase (FAAH) and inhibiting the degradation of endogenous anandamide. To test the role that FAAH plays as a mediator of oleamide activity in vivo, we have compared the behavioral effects of this FAA in FAAH(+/+) and (-/-) mice. In both genotypes, oleamide produced hypomotility, hypothermia, and ptosis, all of which were enhanced in FAAH(-/-) mice, were unaffected by the CB1 antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-di-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) and occurred in CB1(-/-) mice. Additionally, oleamide displayed negligible binding to the CB1 receptor in brain extracts from either FAAH(+/+) or (-/-) mice. In contrast, anandamide exhibited a 15-fold increase in apparent affinity for the CB1 receptor in brains from FAAH(-/-) mice, consistent with its pronounced CB1-dependent behavioral effects in these animals. Contrary to both oleamide and anandamide, monoacylglycerol lipids exhibited equivalent hydrolytic stability and pharmacological activity in FAAH(+/+) and (-/-) mice. Collectively, these results indicate that FAAH is a key regulator, but not mediator of FAA activity in vivo. More generally, these findings suggest that FAAs represent a family of signaling lipids that, despite sharing similar chemical structures and a common pathway for catabolism, produce their behavioral effects through distinct receptor systems in vivo.

subject areas

  • Amides
  • Amidohydrolases
  • Animals
  • Arachidonic Acids
  • Behavior, Animal
  • Blepharoptosis
  • Body Temperature
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Enzyme Inhibitors
  • Fatty Acids
  • Glycerides
  • Kinetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity
  • Oleic Acids
  • Pain Measurement
  • Radioligand Assay
  • Receptors, Cannabinoid
  • Receptors, Drug
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Identity

International Standard Serial Number (ISSN)

  • 0022-3565

Digital Object Identifier (DOI)

  • 10.1124/jpet.302.1.73

PubMed ID

  • 12065702
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Additional Document Info

start page

  • 73

end page

  • 79

volume

  • 302

issue

  • 1

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