Editorial [Hot Topic:The Endocannabinoid System in the Brain: From Biology to Therapy (Guest Editor: Mauro Maccarrone)]

This theme issue is dedicated to my children, Giuseppe and Claudia and to my wife, Gianna. Marijuana is one of the most widely used drugs in the world, and its extracts have been used for centuries in folklore medicine. Yet the identity of its psychoactive constituent, delta-9-tetrahydrocannabinol (Δ9-THC), remained elusive until 1964, when Raphael Mechoulam's group revealed it. Then, the field had to wait until 1988 for the first evidence, presented by Allyn Howlett and colleagues, that a specific cannabinoid receptor exists in the brain. This discovery raised the question of the reason why our brain, as well as most peripheral tissues, contain cannabinoid receptors, that are unlikely to exist in mammalian tissues for the sake of a plant constituent like Δ9-THC. On this background, several groups have started intense research aimed at finding the endogenous ligands of cannabinoid receptors, the so-called "endocannabinoids". Two of such molecules were discovered in the early '90s: N-arachidonoylethanolamine (anandamide) was found in 1992 by Mechoulam's group, and 2- archidonoylglycerol was reported in 1995, independently by the group of Takayuki Sugiura and by that of Mechoulam. Since then the field has attracted growing interest, and a bunch of molecules and proteins have been discovered. These include endocannabinoids and endocannabinoid-like compounds (i.e., amides, esters and ethers of (poly-un)saturated fatty acids), cannabinoid and non-cannabinoid receptors, synthetic and degradative enzymes, as well as membrane transporters, that are at the moment the most debated topic in the field. Overall, these components form the "endocannabinoid system". The growing interest towards this endogenous system of lipids and proteins is demonstrated by the number of papers that appeared in PubMed over the last decade. The word "endocannabinoid" scores 37 entries in 1992-1995, 240 in 1997-2000, and 659 in 2002-2005 ("cannabinoid" scores 428, 911 and 1600 in the same periods of time). If "endocannabinoid" is matched with "central nervous system (CNS)" the entries are 15, 83 and 246, suggesting that more than one third of the field is strictly related to the CNS. The same indication comes from the analysis of "cannabinoid", that counts 106, 298 and 466 entries, when matched with "CNS". Of interest is also the fact that the therapeutic implications of (endo)cannabinoid-oriented drugs have expanded over the last few years, thus the match "endocannabinoid" and "drug development" leads to 0 entries in 1992-1995, 15 in 1997-2000, and 65 in 2002-2005 (for the match with "cannabinoid" the figures are 23, 57 and 146, respectively). As a matter of fact, at least two synthetic cannabinoids are in advanced phase III clinical trials: SR141716 (rimonabant), and HU-211 (dexanabinol). The first compound has been developed by Sanofi-Aventis, and is an appetite modulator; the second compound, developed by Pharmos, is a neuroprotectant in head trauma. Both drugs may represent pharmaceutical breakthroughs in important therapeutic areas of human disease. This brings to the present book. This theme-issue is an outstanding collection of hot topics in the endocannabinoid research, and the review articles should form the basis to better understand the molecular background of the ongoing clinical applications of endocannabinoid-targeted drugs, which have generated great expectations as conceptually new therapeutics. I hope that the aspects of endocannabinoid research summarized in this book may foster novel ideas, boosting investigations into new directions of basic science and clinic, thus ultimately improving our understanding and therapeutic exploitation of the endocannabinoid system.