The Endocannabinoid System as an Emerging Target of Pharmacotherapy
Pál Pacher, Sándor Bátkai and George Kunos

Abstract
I. Introduction
II. The Pharmacology of Cannabinoids
    A. Cannabinoid Receptors and Ligands
    B. Cannabinoid Receptor Signaling
    C. Endocannabinoids
III. The Endocannabinoid System as Therapeutic Target in Pathophysiological Conditions
    A. Diseases of Energy Metabolism
        1. Endocannabinoids and Appetite Regulation
        2. Endocannabinoids and Peripheral Energy Metabolism.
        3. Obesity and Associated Metabolic Abnormalities    
        4. Cachexia and Anorexia
    B. Pain and Inflammation
    C. Central Nervous System Disorders
        1. Neurotoxicity and Neurotrauma
        2. Stroke
        3. Multiple Sclerosis and Spinal Cord Injury
        4. Movement Disorders (Basal Ganglia Disorders)
            a. Parkinson's disease and levodopa-induced dyskinesia
            b. Huntington's disease
            c. Gilles de la Tourette's syndrome, tardive dyskinesia, and dystonia
        5. Amyotrophic Lateral Sclerosis
        6. Alzheimer's Disease
        7. Epilepsy
        8. Mental Disorders
            a. Schizophrenia 
            b. Anxiety and depression
        9. Insomnia
        10. Nausea and Emesis
        11. Drug Addiction and Alcohol Disorders
            a. Opiates
            b. Nicotine
            c. Cocaine
            d. Alcohol
            e. Psychostimulants
    D. Cardiovascular and Respiratory Disorders
        1. Hypertension
        2. Circulatory Shock
        3. Myocardial Reperfusion Injury
        4. Atherosclerosis
        5. Asthma
    E. Eye Disorders (Glaucoma and Retinopathy)
    F. Cancer
    G. Gastrointestinal and Liver Disorders
        1. Inflammatory Bowel Disease
        2. Acute and Chronic Liver Disease (Hepatitis and Liver Cirrhosis)
    H. Musculoskeletal Disorders
        1. Arthritis
        2. Osteoporosis
    I. Endocannabinoids and Reproductive Functions
IV. Future Directions

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 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 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.

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. 

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http://pharmrev.aspetjournals.org/cgi/content/abstract/58/3/389

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