Transporters

Nearly all messenger molecules in the brain (neurotransmitters) are water soluble (hydrophilic). However, to be absorbed by cells, for example for purposes of degradation, passing through the fatty cell membrane would be problematic. To pass the cell membrane, proteins called transporters (to be specific – transmembrane transporters) come to the rescue for these neurotransmitters. For the endocannabinoid system, things are different: endocannabinoids, such as anandamide (AEA), are already fat-loving (lipophilic) and do not like watery environments (hydrophobic), thereby relatively easily diffusing across cell membranes, driven by the concentration gradient inside vs. outside the cell.^{1, 2, 3, 4} In other words, if the concentration of AEA inside the cell decreases, it will trigger an influx of AEA from outside to the inside of the cell. Once inside the watery cell, the problem of how to travel to the appropriate location for degradation arises. Researchers from New York found out that AEA is transported by proteins called Fatty Acid Binding Protein transporters (FABPs).⁵ Changes in drug transporters, either by drug-drug interactions, genetics, or other factors, can change the effects of cannabis.⁶ For example, blocking these transporters can lead to elevation of endogenous cannabinoids and effects in animals, such as inhibition of pain.⁷ References:

1. Day, Theresa A.; Rakhshan, Fariborz; Deutsch, Dale G.; Barker, Eric L. (2001). Role of Fatty Acid Amide Hydrolase in the Transport of the Endogenous Cannabinoid Anandamide. Molecular Pharmacology, 59(6), 1369--1375.
2. Deutsch, Dale G.; Glaser, Sherrye T.; Howell, Judy M.; Kunz, Jeffrey S.; Puffenbarger, Robyn A.; Hillard, Cecilia J.; Abumrad, Nada (2001). The Cellular Uptake of Anandamide is Coupled to its Breakdown by Fatty-acid Amide Hydrolase. Journal of Biological Chemistry, 276(10), 6967--6973.
3. Fowler, Christopher J.; Tiger, Gunnar; Ligresti, Alessia; López-Rodrı́guez, Marı́a L.; Di Marzo, Vincenzo (2004). Selective inhibition of anandamide cellular uptake versus enzymatic hydrolysis—a difficult issue to handle. European Journal of Pharmacology, 492(1), 1--11.
4. Hillard, Cecilia J.; Jarrahian, Abbas (2005). Accumulation of anandamide: Evidence for cellular diversity. Neuropharmacology, 48(8), 1072--1078.
5. Kaczocha, Martin; Glaser, Sherrye T.; Deutsch, Dale G. (2009). Identification of intracellular carriers for the endocannabinoid anandamide. Proceedings of the National Academy of Sciences, 106(15), 6375--6380.
6. Keogh, John; Hagenbuch, Bruno; Rynn, Caroline; Stieger, Bruno; Nicholls, Glynis (2016). Chapter 1 Membrane Transporters: Fundamentals, Function and Their Role in ADME. Drug Transporters: Volume 1: Role and Importance in ADME and Drug Development (1--56). The Royal Society of Chemistry.
7. Berger, William T.; Ralph, Brian P.; Kaczocha, Martin; Sun, Jing; Balius, Trent E.; Rizzo, Robert C.; Haj-Dahmane, Samir; Ojima, Iwao; Deutsch, Dale G. (2012). Targeting Fatty Acid Binding Protein (FABP) Anandamide Transporters – A Novel Strategy for Development of Anti-Inflammatory and Anti-Nociceptive Drugs. PLoS ONE, 7(12), e50968.