(-)-DELTA(9)-TETRAHYDROCANNABINOL ANTAGONIZES THE PERIPHERAL CANNABINOID RECEPTOR-MEDIATED INHIBITION OF ADENYLYL-CYCLASE

(-)-Delta(9)-Tetrahydrocannabinol ((-)-Delta(9)-THC) is the major acti ve psychotropic component of the marijuana plant, Cannabis sativa. The membrane proteins that have been found to bind this material or its d erivatives have been called the cannabinoid receptors. Two GTP-binding protein-coupled cannabinoid receptors have been cloned. CB1 or the ne uronal cannabinoid receptor is found mostly in neuronal cells and tiss ues while CB2 or the peripheral cannabinoid receptor has been detected in spleen and in several cells of the immune system. It has previousl y been shown that activation of CB1 or CB2 receptors by cannabinoid ag onists inhibits adenylyl cyclase activity. Utilizing Chinese hamster o vary cells and COS cells transfected with the cannabinoid receptors we report that (-)-Delta(9)-THC binds to both receptors with similar aff inity. However, in contrast to its capacity to serve as an agonist for the CB1 receptor, (-)-Delta(9)-THC was only able to induce a very sli ght inhibition of adenylyl cyclase at the CB2 receptor. Morever, (-)-D elta(9)-THC antagonizes the agonist-induced inhibition of adenylyl cyc lase mediated by CB2. Therefore, we conclude that (-)-Delta(9)-THC con stitutes a weak antagonist for the CB2 receptor.