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Functional disassociation of the central and peripheral fatty acid amide signaling systems

Academic Article
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Overview

authors

  • Cravatt, Benjamin
  • Saghatelian, Alan
  • Hawkins, E. G.
  • Clement, A. B.
  • Bracey, M. H.
  • Lichtman, A. H.

publication date

  • July 2004

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Fatty acid amides (FAAs) constitute a large class of endogenous signaling lipids that modulate several physiological processes, including pain, feeding, blood pressure, sleep, and inflammation. Although FAAs have been proposed to evoke their behavioral effects through both central and peripheral mechanisms, these distinct signaling pathways have remained experimentally challenging to separate. Here, we report a transgenic mouse model in which the central and peripheral FAA systems have been functionally uncoupled. Mice were generated that express the principle FAA-degrading enzyme FAA hydrolase (FAAH) specifically in the nervous system (FAAH-NS mice) by crossing FAAH(-/-) mice with transgenic mice that express FAAH under the neural specific enolase promoter. FAAH-NS mice were found to possess wild-type levels of FAAs in the brain and spinal cord, but significantly elevated concentrations of these lipid transmitters in peripheral tissues. This anatomically restricted biochemical phenotype correlated with a reversion of the reduced pain sensitivity of FAAH(-/-) mice, consistent with the FAA anandamide producing this effect by acting on cannabinoid receptors in the nervous system. Interestingly, however, FAAH-NS mice still exhibited an antiinflammatory phenotype similar in magnitude to FAAH(-/-) mice, indicating that this activity, which was not blocked by cannabinoid receptor antagonists, was mediated by peripherally elevated FAAs. These data suggest that the central and peripheral FAA signaling systems regulate discrete behavioral processes and may be targeted for distinct therapeutic gain.

subject areas

  • Amides
  • Amidohydrolases
  • Animals
  • Behavior, Animal
  • Central Nervous System
  • Fatty Acids
  • Inflammation
  • Mice
  • Mice, Transgenic
  • Pain
  • Peripheral Nervous System
  • Phenotype
  • Signal Transduction
  • Tissue Distribution
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Identity

PubMed Central ID

  • PMC490018

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0401292101

PubMed ID

  • 15247426
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Additional Document Info

start page

  • 10821

end page

  • 10826

volume

  • 101

issue

  • 29

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