Annu. Rev. Pharmacol. Toxicol. 2006. 46:101–22 doi: 10.1146/annurev.pharmtox.46.120604.141254 Copyright c  2006 by Annual Reviews. All rights reserved First published online as a Review in Advance on August 19, 2005 CANNABINOID RECEPTORS AS THERAPEUTIC T ARGETS Ken Mackie Departments of Anesthesiology and Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington 98195-6540; email: kmackie@u.washington.edu Key Words analgesia, endocannabinoid, fatty acid aminohydrolase, metabolic syndrome, neuroinflammation, obesity ■ Abstract CB1 and CB2 cannabinoid receptors are the primary targets of en- dogenous cannabinoids (endocannabinoids). These G protein–coupled receptors play an important role in many processes, including metabolic regulation, craving, pain, anxiety, bone growth, and immune function. Cannabinoid receptors can be engaged directly by agonists or antagonists, or indirectly by manipulating endocannabinoid metabolism. In the past several years, it has become apparent from preclinical studies that therapies either directly or indirectly influencing cannabinoid receptors might be clinically useful. This review considers the components of the endocannabinoid system and discusses some of the most promising endocannabinoid-based therapies. INTRODUCTION Cannabinoid receptors are part of the endocannabinoid system, which consists of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that synthesize and degrade endocannabinoids. Emerging evidence impli- cates endocannabinoids in a wide variety of physiological and pathophysiological processes. To date, most drugs used therapeutically that interact with the endo- cannabinoid system are derived from cannabis and produce their effects by activa- tion of cannabinoid receptors. Regrettably, the psychoactivity of these compounds has prevented their widespread acceptance and application in Western medicine. In the past decade, the elucidation of the components of the endocannabinoid system and a better understanding of its role have broadened the therapeutic pos- sibilities for its manipulation. For example, cannabinoid receptors can be directly manipulated by ligands that bind cannabinoid receptors or indirectly by drugs that modulate endocannabinoid levels. This review considers the components of the endocannabinoid system, their involvement in specific behaviors and diseases, and several promising clinical and preclinical studies. Because of space limitations not all potential therapies are considered. The interested reader is encouraged to con- sult recent reviews that either offer a different perspective or go into much greater depth on specific indications (1–9). 0362-1642/06/0210-0101$20.00 101 Annu. Rev. Pharmacol. Toxicol. 2006.46:101-122. Downloaded from arjournals.annualreviews.org by UNIVERSITY OF WASHINGTON - HEALTH SCIENCES LIBRARIES on 03/14/06. For personal use only.