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NIH Public Access Author Manuscript Pharmacol Rev. Author manuscript; available in PMC 2008 February 13. NIH-PA Author Manuscript Published in final edited form as: Pharmacol Rev. 2006 September ; 58(3): 389–462. The Endocannabinoid System as an Emerging Target of Pharmacotherapy PÁL PACHER, SÁNDOR BÁTKAI, and GEORGE KUNOS Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland Abstract The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid NIH-PA Author Manuscript amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result NIH-PA Author Manuscript in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients’ need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy. I. Introduction Marijuana, or cannabis, is the most widely used illicit drug in Western societies and also the one with the longest recorded history of human use. The popularity of marijuana as a recreational drug is due to its ability to alter sensory perception and cause elation and euphoria, most vividly described by the 19th century French poet, Charles Baudelaire, in his book Les Paradis Artificiels (Iversen, 2000). However, the ability of extracts of the hemp plant (Cannabis sativa) to cause a variety of medicinal effects unrelated to its psychoactive properties had been recognized as early as the third millennium BC, when Chinese texts described its Address correspondence to: Dr. George Kunos, National Institutes of Health, NIAAA, Laboratory of Physiological Studies, 5625 Fishers Lane, Room 2S-24, Bethesda, MD 20892-9413. E-mail: [email protected]. P.P. and G.K. contributed equally to this work. PACHER et al. Page 2 usefulness in the relief of pain and cramps (Mechoulam, 1986). In ancient India, the anxiety- relieving effect of bhang (the Indian term for marijuana ingested as food) had been recorded NIH-PA Author Manuscript more than 3000 years ago. The use of cannabis or hashish as a psychoactive substance reached Europe and the Americas through the Arab world in the 19th century. During the same period, cannabis extracts had gained widespread use for medicinal purposes until 1937, when concern about the dangers of abuse led to the banning of marijuana for further medicinal use in the United States. The rather turbulent history of marijuana and the recent resurgence of interest in its medicinal properties have been the subject of excellent reviews (Mechoulam, 1986; Iversen, 2000; Di Marzo et al., 2004; Howlett et al., 2004; Pertwee, 2005a; Piomelli, 2005; Di Marzo and Petrocellis, 2006; Mackie, 2006; Pagotto et al., 2006). Added to this interest is the emergence of the endocannabinoid system, offering not only new insights into the mechanisms underlying the therapeutic actions of plant-derived phytocannabinoids but also novel molecular targets for pharmacotherapy. In this overview, we will briefly summarize current thoughts about the role of endocannabinoids in a given physiological or pathological process and then survey attempts to exploit this role for therapeutic gain. II. The Pharmacology of Cannabinoids A. Cannabinoid Receptors and Ligands Up until the last two decades, marijuana research was a rather esoteric field, of interest to a NIH-PA Author Manuscript small number of scientists. A contributory factor was the highly lipophilic nature of the biologically active ingredients, which led to the notion that marijuana elicits its effects nonspecifically by perturbing membrane lipids (Lawrence and Gill, 1975). The first important breakthrough that ultimately led to a rejection of this concept was the identification by Gaoni and Mechoulam (1964) of the correct chemical structure of the main psychoactive ingredient of marijuana, !9-tetrahydrocannabinol (THC1), and the subsequent demonstration that bioactivity resides in the l-stereoisomer of this compound (Mechoulam and Gaoni, 1967), which is one of approximately 60 cannabinoids present in the plant (Dewey, 1986). This discovery stimulated the generation of a whole range of synthetic analogs in the 1970s that included not only compounds structurally similar to phytocannabinoids (Fig. 1A) but also analogs with different chemical structures, including classic and nonclassic cannabinoids and aminoalkylindoles (Fig. 1B) (Howlett et al., 2002), as well as the subsequently discovered endogenous arachidonic acid derivatives or endocannabinoids (Fig. 1C), which are discussed in more detail below. Studies of the biological effects of THC and its synthetic analogs revealed strict structural selectivity (Hollister, 1974) as well as stereo-selectivity (Jones et al., 1974), telltale signs of drug-receptor interactions. Definitive evidence for the existence of specific cannabinoid receptors was followed soon by the demonstration of high-affinity, saturable, stereospecific binding sites for the synthetic cannabinoid agonist [3H]CP-55,940 in mouse NIH-PA Author Manuscript brain plasma membranes, which correlated with both the in vitro inhibition of adenylate cyclase and the in vivo analgesic effect of the compound (Devane et al., 1988). The availability of a radioligand also allowed the mapping of cannabinoid receptors in the brain by receptor autoradiography (Herkenham et al., 1991b). This mapping turned out to be of key importance in the subsequent identification of an orphan G protein-coupled receptor (GPCR) as the brain receptor for cannabinoids (Matsuda et al., 1990), later named CB1 receptor, based on the overlapping regional distribution of the mRNA for this GPCR and [3H]CP-55,940 binding sites. CB1 receptors are the most abundant receptors in the mammalian brain but are also present at much lower concentrations in a variety of peripheral tissues and cells. A second cannabinoid GPCR, CB2, is expressed primarily in cells of the immune and hematopoietic systems (Munro et al., 1993) but recently were found to be present in the brain (Van Sickle et al., 2005; Gong et al., 2006), in nonparenchymal cells of the cirrhotic liver (Julien et al., 2005), in the endocrine pancreas (Juan-Pico et al., 2005), and in bone (Karsak et al., 2004; Idris et al., 2005; Ofek et al., 2006). Two splice variants of CB1 receptors have been also identified: CB1A, which has Pharmacol Rev. Author manuscript; available in PMC 2008 February 13. PACHER et al. Page 3 an altered amino-terminal sequence (Shire et al., 1995), and CB1B, which has an in-frame deletion of 33 amino acids at the amino terminus (Ryberg et al., 2005). The mRNAs of both NIH-PA Author Manuscript splice variants are expressed at much lower levels than the CB1 mRNA and, although the receptors expressed from the cDNAs have unique pharmacology (Ryberg et al., 2005), evidence for their natural expression has not been reported. An interesting twist on the steric selectivity of cannabinoid receptors has emerged through recent studies of the behaviorally inactive phytocannabinoid (")-cannabidiol (CBD) and its synthetic analogs, which have negligible affinity for either CB1 or CB2 receptors. Paradoxically, some of the synthetic (+)-(+)-stereoisomers of these compounds were found to bind potently to both CB1 and CB2 receptors (Bisogno et al., 2001) but to display only peripheral and not centrally mediated cannabinoid-like bioactivity, suggesting that they may act as antagonists rather than agonists at central, but not peripheral, CB1 receptors (Fride et al., 2005). Another ligand