Therapeutic Opportunities through the Modulation of Endocannabinoid

The endocannabinoid system is comprised of cannabinoid receptors (CB1 and CB2), a group of endogenous neuromodulatory lipids (endocannabinoids), and the machinery for their biosynthesis, metabolism, and transit that are involved in a variety of physiological processes including pain, appetite, memory, inflammatory and immune responses. In the brain, endocannabinoids are primarily involved in retrograde signaling, being synthesized and released from postsynaptic neurons to stimulate CB1 receptors located on the presynaptic neurons. Here, we provide an overview of the current research on the transport of endocannabinoids across plasma membranes and their intracellular trafficking with an emphasis on various potential targets for developing therapeutic drugs. The Endocannabinoid System The two most extensively studied endocannabinoids are anandamide (AEA or N-arachidonylethanolamine) and 2-arachidonylglycerol (2-AG). They are believed to be synthesized “on-demand” in response to various physiological stimuli to modulate intracellular secondary messengers upon receptor activation. Imbalances in the endocannabinoid system, either in the central nervous system (CNS) or peripheral tissues, is associated with many types of pathologies. In particular, changes in tissue concentrations of anandamide and 2−arachidonoylglycerol have been observed in pain, inflammation, obesity, neurological and immunological disorders.