Cannabinoid receptors and their ligands in brain and other tissues

Mammalian tissues contain two types of cannabinoid receptor, CB1 and CB2, b oth coupled to their effector systems through G(i/o) proteins. CB1 receptor s are present in the central nervous system as well as in certain neuronal and nonneuronal peripheral tissues. Some CB1 receptors occur at nerve termi nals where they modulate transmitter release when activated. CB2 receptors are found mainly in cells of the immune system. The possibility that mammal ian tissues express additional cannabinoid receptor types of physiological significance cannot be excluded. Indeed, preliminary pharmacological eviden ce supporting this possibility already exists. Endogenous ligands for canna binoid receptors have also been discovered, the most important being arachi donoylethanolamide and 2-arachidonoyl glycerol. These ligands and their rec eptors constitute the endogenous cannabinoid system. The discovery of this system has important physiological, pathophysiological, pharmacological, an d therapeutic implications. Already selective CB1- and CB2-receptor agonist s and antagonists have been developed and two cannabinoid receptor agonists , Delta(9)-tetrahydrocannabinol and nabilone, are used clinically as antiem etics or to boost appetite. Additional therapeutic uses of cannabinoid rece ptor agonists may include the suppression of some multiple sclerosis and sp inal injury symptoms and the management of glaucoma, bronchial asthma, pain , and inflammatory disorders. One possible therapeutic strategy for the fut ure is the development and use of drugs that activate cannabinoid receptors indirectly by modulating extracellular levels of endogenous cannabinoids. CB1-receptor agonists that do not cross the blood-brain barrier or whose po tency is determined more by affinity than efficacy may also have clinical p otential.