Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia

PLoS One. 2014 Apr 4;9(4):e94200. doi: 10.1371/journal.pone.0094200. eCollection 2014.

Abstract

The endocannabinoid anandamide (AEA) is an antinociceptive lipid that is inactivated through cellular uptake and subsequent catabolism by fatty acid amide hydrolase (FAAH). Fatty acid binding proteins (FABPs) are intracellular carriers that deliver AEA and related N-acylethanolamines (NAEs) to FAAH for hydrolysis. The mammalian brain expresses three FABP subtypes: FABP3, FABP5, and FABP7. Recent work from our group has revealed that pharmacological inhibition of FABPs reduces inflammatory pain in mice. The goal of the current work was to explore the effects of FABP inhibition upon nociception in diverse models of pain. We developed inhibitors with differential affinities for FABPs to elucidate the subtype(s) that contributes to the antinociceptive effects of FABP inhibitors. Inhibition of FABPs reduced nociception associated with inflammatory, visceral, and neuropathic pain. The antinociceptive effects of FABP inhibitors mirrored their affinities for FABP5, while binding to FABP3 and FABP7 was not a predictor of in vivo efficacy. The antinociceptive effects of FABP inhibitors were mediated by cannabinoid receptor 1 (CB1) and peroxisome proliferator-activated receptor alpha (PPARα) and FABP inhibition elevated brain levels of AEA, providing the first direct evidence that FABPs regulate brain endocannabinoid tone. These results highlight FABPs as novel targets for the development of analgesic and anti-inflammatory therapeutics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesia*
  • Analgesics / chemistry
  • Analgesics / metabolism
  • Analgesics / pharmacology*
  • Animals
  • Arachidonic Acids / metabolism*
  • Brain / metabolism*
  • Disease Models, Animal
  • Endocannabinoids / metabolism*
  • Fatty Acid-Binding Proteins / antagonists & inhibitors*
  • Fatty Acid-Binding Proteins / chemistry
  • Fatty Acid-Binding Proteins / metabolism
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism
  • Male
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Molecular Docking Simulation
  • Neuralgia / drug therapy
  • Neuralgia / metabolism
  • PPAR alpha / metabolism
  • Polyunsaturated Alkamides / metabolism*
  • Protein Binding
  • Rats
  • Receptor, Cannabinoid, CB1 / metabolism

Substances

  • Analgesics
  • Arachidonic Acids
  • Endocannabinoids
  • Fatty Acid-Binding Proteins
  • PPAR alpha
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1
  • anandamide