The endocannabinoid nervous system: unique opportunities for therapeutic intervention.
The active principle in marijuana, Delta(9)-tetrahydrocannabinol (THC), has been shown to have wide therapeutic application for a number of important medical conditions, including pain, anxiety, glaucoma, nausea, emesis, muscle spasms, and wasting diseases. Delta(9)-THC binds to and activates two known cannabinoid receptors found in mammalian tissue, CB1 and CB2. The development of cannabinoid-based therapeutics has focused predominantly on the CB1 receptor, based on its predominant and abundant localization in the CNS. Like most of the known cannabinoid agonists, Delta(9)-THC is lipophilic and relatively nonselective for both receptor subtypes. Clinical studies show that nonselective cannabinoid agonists are relatively safe and provide therapeutic efficacy, but that they also induce psychotropic side effects. Recent studies of the biosynthesis, release, transport, and disposition of anandamide are beginning to provide an understanding of the role of lipid transmitters in the CNS. This review attempts to link current understanding of the basic biology of the endocannabinoid nervous system to novel opportunities for therapeutic intervention. This new knowledge may facilitate the development of cannabinoid receptor-targeted therapeutics with improved safety and efficacy profiles.
Porter
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Neuroscience Division, Drop 0510, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Felder
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D000581:Amidohydrolases / Q000378:metabolism; D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use; D000932:Antiemetics / Q000627:therapeutic use; D019167:Appetite Stimulants / Q000627:therapeutic use; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism* / Q000627:therapeutic use*; D063388:Endocannabinoids; D005901:Glaucoma / Q000188:drug therapy; D006801:Humans; D009069:Movement Disorders / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000627:therapeutic use; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists*; D015398:Signal Transduction; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D014151:Anti-Anxiety Agents; D000932:Antiemetics; D019167:Appetite Stimulants; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D018696:Neuroprotective Agents; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide