Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications

Abstract

The endocannabinoid system consists of cannabinoid CB 1 and CB 2 receptors, of endogenous agonists for these receptors known as 'endocannabinoids', and of processes responsible for endocannabinoid biosynthesis, cellular uptake and metabolism. There is strong evidence first, that this system up-regulates in certain disorders as indicated by an increased release of endocannabinoids onto their receptors and/or by increases in the expression levels or coupling efficiency of these receptors, and second, that this up-regulation often appears to reduce or abolish unwanted effects of these disorders or to slow their progression. This discovery has raised the possibility of developing a medicine that enhances up-regulation of the endocannabinoid system associated with these disorders by inhibiting the cellular uptake or intracellular metabolism of an endocannabinoid following its 'autoprotective' endogenous release. For inhibition of endocannabinoid metabolism, research has focused particularly on two highly investigated endocannabinoids, anandamide and 2-arachidonoyl glycerol, and hence on inhibitors of the main anandamide-metabolising enzyme, fatty acid amide hydrolase (FAAH), and of the main 2-arachidonoyl glycerolmetabolising enzyme, monoacylglycerol (MAG) lipase. The resulting data have provided strong preclinical evidence that selective FAAH and MAG lipase inhibitors would ameliorate the unwanted effects of several disorders, when administered alone or with a cyclooxygenase inhibitor, and that the benefit-to-risk ratio of a FAAH inhibitor would exceed that of a MAG lipase inhibitor or dual inhibitor of FAAH and MAG lipase. Promising preclinical data have also been obtained with inhibitors of endocannabinoid cellular uptake. There is now an urgent need for clinical research with these enzyme and uptake inhibitors. Fatty acid amide hydrolase inhibitors: Monoacylglycerol lipase inhibitors:Endocannabinoids: Anandamide and 2-arachidonoyl glycerol: Cannabinoid CB 1 and CB 2 receptorsEndocannabinoids are endogenously produced compounds that can target cannabinoid CB 1 and/or CB 2 receptors, both of which are G protein-coupled. The most investigated of these endocannabinoids have been arachidonoylethanolamide (anandamide) and 2-arachidonoyl glycerol, each of which can activate both CB 1 and CB 2 receptors (1) . Endocannabinoids and cannabinoid CB 1 and CB 2 receptors, together with the processes responsible for endocannabinoid biosynthesis, cellular uptake and metabolism, constitute the 'endocannabinoid system' (2) . Importantly, there is convincing evidence, albeit mainly from animal experiments, that there are a number of disorders in which the endocannabinoid system up-regulates in a manner that reduces or abolishes

The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

“…Dual FAAH/MAGL inhibition and using peripherally restricted inhibitors of FAAH and MAGL are also among the promising strategies (38,39,48). Moving to the inhibition of endocannabinoid cellular uptake, there are some potential therapeutic effects observed with the use of membrane transporter inhibitors in animal models (30,38,40).…”

“…Reducing the cannabinoid and opioid/NSAID dose needed may provide an advantageous treatment strategy by enhancing pain relief whilst minimising the incidence of adverse effects (6,7,37). Elevating endocannabinoid levels appears to be the most striking strategy for developing analgesic drugs with cannabinoid properties but devoid of central psychotropic effects (38)(39)(40). During pain states, endocannabinoids are only synthesised and metabolised in the CNS structures involved in pain transmission and modulation.…”

“…Thus, augmenting endocannabinoid levels in these structures will only effect CB receptors in these areas and possibly reduce central side effects. Inhibition of the degradative enzymes FAAH and MAGL, and inhibition of endocannabinoid cellular uptake are the pharmacological strategies used to modulate the endocannabinoid system and elevate endocannabinoid levels locally (3,5,22,38,40).…”

“…Thus, augmenting endocannabinoid levels in these structures will only effect CB receptors in these areas and possibly reduce central side effects. Inhibition of the degradative enzymes FAAH and MAGL, and inhibition of endocannabinoid cellular uptake are the pharmacological strategies used to modulate the endocannabinoid system and elevate endocannabinoid levels locally (3,5,22,38,40).Fatty acid amide hydrolase inhibitors, such as URB597 and OL135, are shown to be effective at reducing sensitivity to pain in acute and chronic experimental pain models (41,42). However, in a recent clinical trial, PF-04457845, an irreversible FAAH inhibitor, failed to induce effective analgesia in patients with knee osteoarthritis (43).…”

Fatty Acid Amide Hydrolase Inhibition by JNJ‐42165279: A Multiple‐Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers

“…Activation of cannabinoid receptors by endogenous lipids (endocannabinoids) in the central nervous system (CNS) is hypothesized to provide homeostatic regulation through negative feedback inhibition of excitatory pathways 1. Endocannabinoid activity can be enhanced by inhibition of fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for degrading a variety of fatty acid amides (FAAs) 2. FAAs are a group of signaling lipids that participate in the control of many physiological processes including pain, cognition, mood regulation, sleep, energy metabolism, and inflammation.…”