HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pacher, P. Articles by Kunos, G. Search for Related Content PubMed PubMed Citation Articles by Pacher, P. Articles by Kunos, G.

Review Article

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland

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.

This article has been cited by other articles:

				A A Izzo and M Camilleri Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects Gut, August 1, 2008; 57(8): 1140 - 1155. [Abstract] [Full Text] [PDF]

				M. Duncan, A. Mouihate, K. Mackie, C. M. Keenan, N. E. Buckley, J. S. Davison, K. D. Patel, Q. J. Pittman, and K. A. Sharkey Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats Am J Physiol Gastrointest Liver Physiol, July 1, 2008; 295(1): G78 - G87. [Abstract] [Full Text] [PDF]

				V. L. Hegde, S. Hegde, B. F. Cravatt, L. J. Hofseth, M. Nagarkatti, and P. S. Nagarkatti Attenuation of Experimental Autoimmune Hepatitis by Exogenous and Endogenous Cannabinoids: Involvement of Regulatory T Cells Mol. Pharmacol., July 1, 2008; 74(1): 20 - 33. [Abstract] [Full Text] [PDF]

				A. W. Herling, S. Kilp, R. Elvert, G. Haschke, and W. Kramer Increased Energy Expenditure Contributes More to the Body Weight-Reducing Effect of Rimonabant than Reduced Food Intake in Candy-Fed Wistar Rats Endocrinology, May 1, 2008; 149(5): 2557 - 2566. [Abstract] [Full Text] [PDF]

				G. Kunos and D. Osei-Hyiaman Endocannabinoids and Liver Disease. IV. Endocannabinoid involvement in obesity and hepatic steatosis Am J Physiol Gastrointest Liver Physiol, May 1, 2008; 294(5): G1101 - G1104. [Abstract] [Full Text] [PDF]

				F. SCHINDLER, I. ANGHELESCU, F. REGEN, and M. JOCKERS-SCHERUBL Improvement in Refractory Obsessive Compulsive Disorder With Dronabinol Am J Psychiatry, April 1, 2008; 165(4): 536 - 537. [Full Text] [PDF]

				P. Pacher and B. Gao Endocannabinoids and Liver Disease. III. Endocannabinoid effects on immune cells: implications for inflammatory liver diseases Am J Physiol Gastrointest Liver Physiol, April 1, 2008; 294(4): G850 - G854. [Abstract] [Full Text] [PDF]

				A. Ludanyi, L. Eross, S. Czirjak, J. Vajda, P. Halasz, M. Watanabe, M. Palkovits, Z. Magloczky, T. F. Freund, and I. Katona Downregulation of the CB1 Cannabinoid Receptor and Related Molecular Elements of the Endocannabinoid System in Epileptic Human Hippocampus J. Neurosci., March 19, 2008; 28(12): 2976 - 2990. [Abstract] [Full Text] [PDF]

				F. Montecucco, F. Burger, F. Mach, and S. Steffens CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1145 - H1155. [Abstract] [Full Text] [PDF]

				P. Pacher and Z. Ungvari Pleiotropic effects of the CB2 cannabinoid receptor activation on human monocyte migration: implications for atherosclerosis and inflammatory diseases Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1133 - H1134. [Full Text] [PDF]

				J. Munoz-Luque, J. Ros, G. Fernandez-Varo, S. Tugues, M. Morales-Ruiz, C. E. Alvarez, S. L. Friedman, V. Arroyo, and W. Jimenez Regression of Fibrosis after Chronic Stimulation of Cannabinoid CB2 Receptor in Cirrhotic Rats J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 475 - 483. [Abstract] [Full Text] [PDF]

				W. Xiong, M. Hosoi, B.-N. Koo, and L. Zhang Anandamide Inhibition of 5-HT3A Receptors Varies with Receptor Density and Desensitization Mol. Pharmacol., February 1, 2008; 73(2): 314 - 322. [Abstract] [Full Text] [PDF]

				A. Mallat and S. Lotersztajn Endocannabinoids and Liver Disease. I. Endocannabinoids and their receptors in the liver Am J Physiol Gastrointest Liver Physiol, January 1, 2008; 294(1): G9 - G12. [Abstract] [Full Text] [PDF]

				M. Camilleri, P. Carlson, S. McKinzie, A. Grudell, I. Busciglio, D. Burton, K. Baxter, M. Ryks, and A. R. Zinsmeister Genetic variation in endocannabinoid metabolism, gastrointestinal motility, and sensation Am J Physiol Gastrointest Liver Physiol, January 1, 2008; 294(1): G13 - G19. [Abstract] [Full Text] [PDF]

				M. Rajesh, H. Pan, P. Mukhopadhyay, S. Batkai, D. Osei-Hyiaman, G. Hasko, L. Liaudet, B. Gao, and P. Pacher Pivotal Advance: Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis J. Leukoc. Biol., December 1, 2007; 82(6): 1382 - 1389. [Abstract] [Full Text] [PDF]

				H. F. Rosenberg Endocannabinoids, cannabinoid receptors and inflammatory stress: an interview with Dr. Pal Pacher J. Leukoc. Biol., December 1, 2007; 82(6): 1390 - 1392. [Full Text] [PDF]

				A. Telek, T. Biro, E. Bodo, B. I. Toth, I. Borbiro, G. Kunos, and R. Paus Inhibition of human hair follicle growth by endo- and exocannabinoids FASEB J, November 1, 2007; 21(13): 3534 - 3541. [Abstract] [Full Text] [PDF]

				C. E. Spivak, C. R. Lupica, and M. Oz The Endocannabinoid Anandamide Inhibits the Function of {alpha}4beta2 Nicotinic Acetylcholine Receptors Mol. Pharmacol., October 1, 2007; 72(4): 1024 - 1032. [Abstract] [Full Text] [PDF]

				M. Rajesh, P. Mukhopadhyay, S. Batkai, G. Hasko, L. Liaudet, J. W. Huffman, A. Csiszar, Z. Ungvari, K. Mackie, S. Chatterjee, et al. CB2-receptor stimulation attenuates TNF-{alpha}-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2210 - H2218. [Abstract] [Full Text] [PDF]

				F. Niyuhire, S. A. Varvel, B. R. Martin, and A. H. Lichtman Exposure to Marijuana Smoke Impairs Memory Retrieval in Mice J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1067 - 1075. [Abstract] [Full Text] [PDF]

				A. W. Herling, M. Gossel, G. Haschke, S. Stengelin, J. Kuhlmann, G. Muller, D. Schmoll, and W. Kramer CB1 receptor antagonist AVE1625 affects primarily metabolic parameters independently of reduced food intake in Wistar rats Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E826 - E832. [Abstract] [Full Text] [PDF]

				S. Batkai, P. Mukhopadhyay, J. Harvey-White, R. Kechrid, P. Pacher, and G. Kunos Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1689 - H1695. [Abstract] [Full Text] [PDF]

				P. Mukhopadhyay, S. Batkai, M. Rajesh, N. Czifra, J. Harvey-White, G. Hasko, Z. Zsengeller, N. P. Gerard, L. Liaudet, G. Kunos, et al. Pharmacological Inhibition of CB1 Cannabinoid Receptor Protects Against Doxorubicin-Induced Cardiotoxicity J. Am. Coll. Cardiol., August 7, 2007; 50(6): 528 - 536. [Abstract] [Full Text] [PDF]

				G. Fajardo and D. Bernstein Endocannabinoid Inhibition: A New Cardioprotective Strategy Against Doxorubicin Cardiotoxicity J. Am. Coll. Cardiol., August 7, 2007; 50(6): 537 - 539. [Full Text] [PDF]

				S. Batkai, M. Rajesh, P. Mukhopadhyay, G. Hasko, L. Liaudet, B. F. Cravatt, A. Csiszar, Z. Ungvari, and P. Pacher Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H909 - H918. [Abstract] [Full Text] [PDF]

				E. Benarroch Endocannabinoids in basal ganglia circuits: Implications for Parkinson disease Neurology, July 17, 2007; 69(3): 306 - 309. [Full Text] [PDF]

				T. Esfandyari, M. Camilleri, I. Busciglio, D. Burton, K. Baxter, and A. R. Zinsmeister Effects of a cannabinoid receptor agonist on colonic motor and sensory functions in humans: a randomized, placebo-controlled study Am J Physiol Gastrointest Liver Physiol, July 1, 2007; 293(1): G137 - G145. [Abstract] [Full Text] [PDF]

				M. Rajesh, P. Mukhopadhyay, S. Batkai, G. Hasko, L. Liaudet, V. R. Drel, I. G. Obrosova, and P. Pacher Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H610 - H619. [Abstract] [Full Text] [PDF]

				S. Batkai, D. Osei-Hyiaman, H. Pan, O. El-Assal, M. Rajesh, P. Mukhopadhyay, F. Hong, J. Harvey-White, A. Jafri, G. Hasko, et al. Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury FASEB J, June 1, 2007; 21(8): 1788 - 1800. [Abstract] [Full Text] [PDF]

				G. Turu, A. Simon, P. Gyombolai, L. Szidonya, G. Bagdy, Z. Lenkei, and L. Hunyady The Role of Diacylglycerol Lipase in Constitutive and Angiotensin AT1 Receptor-stimulated Cannabinoid CB1 Receptor Activity J. Biol. Chem., March 16, 2007; 282(11): 7753 - 7757. [Abstract] [Full Text] [PDF]

				M. Bluher, S. Engeli, N. Kloting, J. Berndt, M. Fasshauer, S. Batkai, P. Pacher, M. R. Schon, J. Jordan, and M. Stumvoll Dysregulation of the Peripheral and Adipose Tissue Endocannabinoid System in Human Abdominal Obesity Diabetes, November 1, 2006; 55(11): 3053 - 3060. [Abstract] [Full Text] [PDF]