Fatty Acid Binding Protein Deletion Suppresses Inflammatory Pain through Endocannabinoid/N-Acylethanolamine-Dependent Mechanisms

Abstract

BackgroundFatty acid binding proteins (FABPs) serve as intracellular carriers that deliver endocannabinoids and N-acylethanolamines to their catabolic enzymes. Inhibition of FABPs reduces endocannabinoid transport and catabolism in cells and FABP inhibitors produce antinociceptive and anti-inflammatory effects in mice. Potential analgesic effects in mice lacking FABPs, however, have not been tested.FindingsMice lacking FABP5 and FABP7, which exhibit highest affinities for endocannabinoids, possessed elevated levels of the endocannabinoid anandamide and the related N-acylethanolamines palmitoylethanolamide and oleoylethanolamide. There were no compensatory changes in the expression of other FABPs or in endocannabinoid-related proteins in the brains of FABP5/7 knockout mice. These mice exhibited reduced nociception in the carrageenan, formalin, and acetic acid tests of inflammatory and visceral pain. The antinociceptive effects in FABP5/7 knockout mice were reversed by pretreatment with cannabinoid receptor 1, peroxisome proliferator-activated receptor alpha, and transient receptor potential vanilloid 1 receptor antagonists in a modality specific manner. Lastly, the knockout mice did not possess motor impairments.ConclusionsThis study demonstrates that mice lacking FABPs possess elevated levels of N-acylethanolamines, consistent with the idea that FABPs regulate the endocannabinoid and N-acylethanolamine tone in vivo. The antinociceptive effects observed in the knockout mice support a role for FABPs in regulating nociception and suggest that these proteins should serve as targets for the development of future analgesics.

Female Mice are Resistant to Fabp1 Gene Ablation‐Induced Alterations in Brain Endocannabinoid Levels

“…Ablation/inhibition of cytosolic ‘chaperones’ is known to decrease NAE and 2-MG targeting for degradation which in turn increases their level (38, 47, 79). Since LKO decreased brain levels of non-ARA NAEs and 2-MGs, this would suggest that the concomitant upregulation of FABP3 may have exerted a larger impact than downregulation of the other cytosolic ‘chaperones’ which were either decreased or unchanged.…”

“…Sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis was performed on brain post-nuclear supernatants (PNS) as described earlier (17, 46, 47). Brain proteins were resolved by 12% Tris-SDS-PAGE gel, transferred to 0.2 μm nitrocellulose membrane (162-0112, BioRad Laboratories, Hercules, CA), blocked with 3% gelatin for 1 hr, and incubated overnight with select primary antibodies followed by species-specific Horseradish Peroxidase (HRP) or Alkaline Phosphatase (AP) conjugated secondary antibodies for 1–2 hr.…”

Fatty Acid Binding Protein‐1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias

“…The net effect of FABP1 gene ablation mediated changes in brain endocannabinoid levels on other brain functions remains to be elucidated. Since ablation or inhibition of FABPs 3,5, and 7 in brain is known to markedly impact such parameters (108, 172), whether FABP1 gene ablation alters behavior, pain and inflammation remains an intriguing possibility.…”

FABP1: A Novel Hepatic Endocannabinoid and Cannabinoid Binding Protein

“…FABP3, FABP5, FABP7) all bind arachidonic acid (ARA)-derived EC (AEA, 2-AG) and cannabinoids (4–6). Importantly, pharmacological inhibition or ablation of these FABPs found in brain inhibits EC degradation, thereby enhancing EC accumulation and physiological action in brain (7–10). Surprisingly, although the liver form of fatty acid binding protein (FABP1) is not detectable in brain (11–13), nevertheless ablation of FABP1 markedly increases brain EC levels—especially AEA and 2-AG (13).…”