Certainly, Fu and colleagues did screen a big library of man made compounds for his or her activity to bind to FLAT and inhibit anandamide cellular uptake, and came up having a novel compound, ARN272 (Figure ?(Shape4),4), which inhibits Even however, not FAAH-1 competitively, and exerts potent antihyperalgesic activities in types of inflammatory and acute agony, in a way attenuated by a CB1 receptor antagonist.70 Despite its potential relevance to the development of future analgesics, does the discovery of FLAT really negate the existence of an EMT process? The fact that FLAT is inhibited by some of those compounds that were previously suggested to be selective for the EMT versus FAAH-1 (i.e., OMDM-1 and AM1172)70 (Figure ?(Figure4)4) might support this possibility. roles different from those of cannabinoid receptors. These peculiarities of endocannabinoid signaling have complicated the use of inhibitors of its inactivation mechanisms as a safer and more efficacious alternative to the direct targeting of cannabinoid receptors for the treatment of several pathological conditions, including pain. However, new strategies, including the rediscovery of dirty drugs, and the use of certain natural products (including non-THC cannabis constituents), are emerging that might allow us to make a virtue of necessity and exploit endocannabinoid redundancy to develop new analgesics. preparations, such as marijuana, can alleviate pain in humans has been known for millennia. However, the realization that plant cannabinoids, and 9-tetraydrocannabinol (THC) in particular, strongly reduce nociception in animal models of acute, visceral, inflammatory, and chronic pain, is relatively more recent.1 The cloning in the 1990s of G-protein-coupled receptors for THC, the cannabinoid type-1 and -2 receptors (CB1 and CB2),2,3 strongly expressed in neurons and immune cells (including microglia), respectively, provided a molecular mechanism for these therapeutically promising effects and raised expectations that they could be soon translated into new analgesic and anti-inflammatory medicines. Yet, the possibility arose that direct activation of CB1 and CB2 with either natural of synthetic agonists might also produce unwanted effects in terms of psychotropic and immunosuppressive actions,1,4 respectively. Therefore, the subsequent discovery of endogenous agonists of cannabinoid receptors, known as endocannabinoids,5 and of the molecular mechanisms and enzymes controlling their biosynthesis and inactivation, appeared to provide new solutions to this dilemma. In fact, it became soon clear that, unlike neurotransmitters, hormones, and other mediators, and similar to other derivatives of arachidonic acid (eicosanoids) often involved in pain and inflammation, the two most studied endocannabinoids, enantiomers of ibuprofen, naproxen, and flurbiprofen (Figure ?(Figure3),3), despite their relatively weak inhibitory effect on COX-2-mediated oxidation of arachidonic acid, are potent inhibitors of the oxidation of endocannabinoids by this enzyme. Therefore, (constituent, cannabidiol (Figure ?(Figure3),3), which belongs to the same chemical class as THC but is devoid of potent direct actions at CB1 and CB2 Voruciclib hydrochloride receptors, has proven to be very efficacious against inflammation and pain. Cannabidiol was suggested to exert these effects via several targets, including stimulation/desensitization of TRPV1 and TRPA1,62 and inhibition of endocannabinoid62 and adenosine63 inactivation.64?66 In summary, both natural and (old and new) synthetic compounds with more than one mechanism of action seem to have revived the importance of dirty drugs, which may now Voruciclib hydrochloride provide us with new strategies to deal with endocannabinoid redundancy and treat pain and inflammation . Analgesia through Inhibition of Endocannabinoid Cellular Uptake: The FLAT Truth? Another strategy to treat pain that has been so far explored only in preclinical studies Prokr1 is the one based on the inhibition of the putative endocannabinoid membrane transporter (EMT), the existence of which has been dwelled upon for Voruciclib hydrochloride over 15 years.9 In fact, hydrolysis or oxidation of endocannabinoids is effected at the intracellular level, and although these mediators are lipophilic and can cross the plasma membrane by simple passive diffusion, there is indirect evidence for the existence of a membrane transporter-like process facilitating this passage according to the gradient of concentrations, and in a manner subject to regulation by other mediators.9 However, the fact that no protein has been identified so far to specifically facilitate endocannabinoid transport across the membrane, has cast doubts over the existence of the EMT and hindered the development of truly selective as well as potent inhibitors of this process. Furthermore, the observation that several intracellular proteins bind anandamide with varying.