A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs)

Abstract

This perspective was adapted from a Career Achievement Award talk given at the International Cannabinoid Research Society Symposium in Bukovina, Poland on June 27, 2016. As a biochemist working in the neurosciences, I was always fascinated with neurotransmitter inactivation. In 1993 we identified an enzyme activity that breaks down anandamide. We called the enzyme anandamide amidase, now called FAAH. We and other laboratories developed FAAH inhibitors that were useful reagents that also proved to have beneficial physiological effects and until recently, new generations of inhibitors were in clinical trials. Nearly all neurotransmitters are water soluble and as such, require a transmembrane protein transporter to pass through the lipid membrane for inactivation inside the cell. However, using model systems, we and others have shown that this is unnecessary for anandamide, an uncharged hydrophobic molecule that readily diffuses across the cellular membrane. Interestingly, its uptake is driven by the concentration gradient resulting from its breakdown mainly by FAAH localized in the endoplasmic reticulum. We identified the FABPs as intracellular carriers that “solubilize” anandamide, transporting anandamide to FAAH. Compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids (THC and CBD) also were discovered to bind FABPs and this may be one of the mechanisms by which CBD works in childhood epilepsy, raising anandamide levels. Targeting FABPs may be advantageous since they have some tissue specificity and do not require reactive serine hydrolase inhibitors, as does FAAH, with potential for off-target reactions. At the International Cannabis Research Society Symposium in 1992, Raphe Mechoulam revealed that his laboratory isolated an endogenous lipid molecule that binds to the CB1 receptor (cannabinoid receptor type 1) and this became the milestone paper published in December of that year describing anandamide (AEA, Devane et al., 1992). As to be expected, this discovery raised the issues of AEA's synthesis and breakdown.

The Antinociceptive Agent SBFI-26 Binds to Anandamide Transporters FABP5 and FABP7 at Two Different Sites

“…Inhibition of FABPs reduces AEA inactivation in vitro and elevates AEA levels in vivo 4, 6–8 . Thus, FABP5 and FABP7 are novel targets for modulating AEA levels and signaling pathways 9, 10 .…”

Sterol Carrier Protein‐2/Sterol Carrier Protein‐x/Fatty Acid Binding Protein‐1 Ablation Impacts Response of Brain Endocannabinoid to High‐Fat Diet

“…The brain expresses four other cytosolic binding/“Chaperone” proteins [FABP3, FABP5, FABP7, and heat shock protein‐70 (HSP70)], which transport AEA to the endoplasmic reticulum for degradation by FAAH (Deutsch, ; Kaczocha et al, , ). TKO alone decreased the brain FABP3 (Fig.…”

“…membrane), target to sites of action, facilitate reuptake, and traffic to sites of degradation in the brain (rev. in (Deutsch, ; Kaczocha et al, ; Schroeder et al, ). Whether any of these FABP found in the brain also bind/“Chaperone” the other major ARA‐containing EC, that is, 2‐AG, to intracellular sites of degradation by MAGL is not known.…”

Opioid‐sparing effects of cannabinoids on morphine analgesia: participation of CB1 and CB2 receptors

“…Inhibition of this enzyme will result in an increase in endogenous anandamide levels. Recently, inhibitors of FAAH have been investigated as potential therapeutic targets for pain and CNS disorders (Ahn, Johnson, & Cravatt, ; Deutsch, ). Our results show that GP1a has analgesic activity on chronic/tonic pain by itself, as well as increasing morphine's effect on inflammatory pain.…”

“…Inhibition of this enzyme will result in an increase in endogenous anandamide levels. Recently, inhibitors of FAAH have been investigated as potential therapeutic targets for pain and CNS disorders (Ahn, Johnson, & Cravatt, 2009;Deutsch, 2016).…”