Inhibition of Fatty Acid Binding Proteins Elevates Brain Anandamide Levels and Produces Analgesia

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.

Fatty Acid-binding Proteins (FABPs) Are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)

“…In vitro experiments confirmed that these cannabinoids bind the FABPs, all with a low micromolar affinity (1.04 -3.14 M). Interestingly, these affinities are only slightly lower than those observed with SBFI26, a truxillic acid compound recently identified as a specific inhibitor of the FABPs (K i for FABP3, FABP5, and FABP7 ϭ 3.86 Ϯ 0.70, 0.93 Ϯ 0.08, and 0.38 Ϯ 0.04, respectively) (16). However, unlike SBFI26, THC and CBD showed pronounced affinity for FABP3.…”

“…8). Indeed, inhibition of FABPs was recently shown to elevate brain levels of AEA in mice (16,62). This proposed mechanism of AEA modulation in humans is highly dependent on the pharmacological concentrations of cannabinoids in the brain following consumption.…”

Mina tratatzeko estrategia farmakologiko berriak: kannabinoideak

“…CBDak anandamidaren degradazio-entzima (FAAH) inhibi dezake in vitro (19,20) eta gizakietan dagoeneko frogatu den moduan anandamidaren kontzentrazioa garunean handitu (26). Gaitasun horrek, esaterako, CBDaren psikosiaren kontrako efektuak azaltzen dituela ikusita (26), minerako ere antzekoa gerta daitekeela iradoki genezake (27). Hala ere, CBDaren gaitasun analgesikoaren inguruko ebidentziak eskasak izanik, ez dago argi zeharkako efektu hori analgesia eragiteko nahikoa den.…”

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

“…The compound was active in the acetic acid model of visceral pain, an effect blocked by rimonabant and the peroxisome proliferator-activated receptor α (PPARα) antagonist GW6471. No overt cannabinoid-like effects upon locomotion were seen (Berger et al 2012;Kaczocha et al 2014). The effects of SB-FI-26 upon neuropathic pain were less convincing: in the chronic constriction injury (CCI) model of neuropathic pain in male Fisher 344 rats, it produced a short-term effect upon thermal hyperalgesia, but was without effect upon mechanical hyperalgesia (Kaczocha et al 2014).…”

“…No overt cannabinoid-like effects upon locomotion were seen (Berger et al 2012;Kaczocha et al 2014). The effects of SB-FI-26 upon neuropathic pain were less convincing: in the chronic constriction injury (CCI) model of neuropathic pain in male Fisher 344 rats, it produced a short-term effect upon thermal hyperalgesia, but was without effect upon mechanical hyperalgesia (Kaczocha et al 2014). It is not known if SB-FI-26 produces the same sort of memory and learning deficits as those seen in FABP5 À/À mice (Yu et al 2014).…”