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Vincenzo Di Marzo was born in Naples, Italy, in 1960, and did his first degree in chemistry in 1983 at the University of Naples 'Federico II', and his Ph.D. in biochemistry at Imperial College of Science, Technology and Medicine, London, UK, in 1988. At present, he is First Researcher at the Institute of Biomolecular Chemistry of Consiglio Nazionale delle Ricerche (CNR), Pozzuoli, Naples, Italy, where he has been a resident since 1988. He is also Adjunct Associate Professor at the Medical College of Virginia, Virgina Commonwealth University, Richmond, Virgina, USA. From 1994 to 1997 he was the principal investigator of a Human Frontier Science Program research grant to study the biosynthesis and metabolism of anandamide. He was the principal investigator of a 3-year European Community-funded research project to study the immunomodulatory role of endocannabinoids. He is currently also responsible for a unit of the CNR in Pozzuoli funded by the VolkswagenStiftung to work on the role of endocannabinoids in memory. He is currently President of the International Cannabinoid Research Society.
Maurizio Bifulco was born in Naples, Italy, in 1956. He did his M.D. degree in 1980 at the University of Naples 'Federico II'. From 1982 to 1983 he was a visiting fellow at the Laboratory of Biochemical Pharmacology, National Institues of Health, Bethesda, Maryland, USA. From 1982 to 1987 he took a fellowship at the Center of Endocrinology and Experimental Oncology of CNR, Naples, Italy. In 1984 he became Resident in Endocrinology. From 1987 to 1992 he was Assistant Professor, and from 1992 to 2001, Associate Professor of General Pathology at University of Catanzaro, Medical School, Italy. Since 2001 he has been Full Professor of General Pathology at the Faculty of Pharmacy, University of Salerno.
Luciano De Petrocellis was born in Naples, Italy, in 1955. He did his first degree in chemistry in 1979 at the University of Naples 'Federico II'. In 1980 he was a postdoctoral researcher in enzymology at the Istituto 'Mario Negri' in Milan, Italy. In 1982 he became a permanent researcher at the Institute of Cybernetics of CNR, Pozzuoli, Naples, and then, in 2001, First Researcher at this same institute. Since 1985 he has been Head of the Cellular Systems at the Institute of Cybernetics.
The term 'endocannabinoid' — originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Δ9-tetrahydrocannabinol and their endogenous ligands — now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.
Cannabis has long been used for the relief of cramps and rheumatic pain, and in 1964 its main psychoactive ingredient — (−)-Δ9-tetrahydrocannabinol (THC) — was finally isolated and characterized.
The development by Pfizer of a non-classical cannabinoid led to the cloning of the first cannabinoid receptor, CB1, which was swiftly followed in 1993 by the cloning of the second receptor, CB2, and the isolation of endogenous ligands, the endocannabinoids, in 1992–1995.
Knowledge of the physiological function of the cannabinoid system is still emerging. However, the pathological alteration of cannabinoid signalling has been observed in psychiatric disorders; stroke; neurodegenerative conditions such as Parkinson's and Alzheimer's diseases; cancer; reproductive, cardiovascular and gastrointestinal disorders; and, perhaps most famously, in multiple sclerosis, making this signalling pathway a cornucopia of potential therapeutic targets.
Many of the enzymes involved in endocannabioid synthesis and degradation have now been characterized and are currently being pursued as therapeutic targets, including N-acylphosphatidylethanolamine-selective phospholipase D, fatty acid amide hydrolase, diacylglycerol lipase isozymes α and β, and monoacylglycerol lipase.
Other therapeutic strategies include small-molecule cannabinoid receptor agonists and antagonists, and the use of non-psychotropic plant cannabinoids. A CB1 receptor antagonist looks promising against obesity, metabolic syndrome and nicotine dependence after completing initial Phase III clinical trials. Clinical trials carried out so far with oral THC and plant cannabinoids for the treatment of multiple sclerosis and Parkinson's disease have shown some efficacy and few side effects.
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The work of the authors is currently supported by grants from the Ministry of Italian University and Research (MIUR, Fondo Italiano per la Ricerca di Base, to V.D.M.), the Volkswagen Stiftung (to V.D.M.), GW Pharm Ltd (to V.D.M., M.B. and L.D.P.), the Associazione Italiana per la Ricerca sul Cancro (AIRC, to M.B.) and the Associazione ERMES (to M.B.).
Endocannabinoid Research Group, Institutes of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Napoli, Italy.
Endocannabinoid Research Group, Institutes of Cybernetics, National Research Council, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Napoli, Italy.
V.D.M, M.B. and L.D.P. receive research funding from G. W. Pharm and Sanofi-Synthelabo.
Correspondence to Vincenzo Di Marzo.
(THC). The major psychotropic component of Cannabis sativa, and one of about 66 'cannabinoids' found in the flowers of this plant.
Natural lipophilic products from the flower of Cannabis sativa, most of which have a typical bi-cyclic or tri-cyclic structure and a common biogenetic origin from olivetol.
G-protein-coupled receptors for THC, so far identified in most vertebrate phyla. Two subtypes are known: CB1 and CB2.
Endogenous agonists of cannabinoid receptors in animal organisms.
One of the most studied endocannabinoids, named from the Sanskrit word 'ananda' for 'bliss'.
A physiological action consisting of the capability of modulating neurotransmitter release and/or action.
Putative and elusive membrane protein(s) that has (have) been postulated to be capable of binding selectively to the endocannabinoids and to facilitate their transport across the plasma membrane according to concentration gradients.
Methodologies for quantifying the levels of the endocannabinoids and of cannabinoid receptors, consisting mostly of isotope-dilution mass-spectrometric techniques for anandamide and 2-AG, polymerase chain reaction and in situ hybridization techniques for receptor and enzyme mRNAs, western immunoblotting and immunohistochemistry for receptor and enzyme proteins.
A typical property of the production of endocannabinoids, which are made in the organism only 'when and where needed'.
Any plant or synthetic cannabinoid-like compound that does not induce, in animal models and in humans, the central cannabimimetic effects typical of THC.
Any receptor agonist that does not induce a full functional response in a given functional assay of receptor activation.

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