Cannabinoid Receptors.

Considerable progress has been made in understanding how cannabinoids exert their cellular effects. To date, 2 types of cannabinoid receptors (CB1¬ and CB2) have been identified. Cannabinoid receptors are coupled to G-proteins, inhibiting adenylate cyclase in a pertussis-toxin sensitive manner, and activating protein kinase. CB1 receptors inhibit voltage-gated calcium channels and increase potassium conductance. Other effector systems for cannabinoid receptors also have been proposed.

Central nervous system (CNS) responses to cannabinoids are mediated by CB1 receptors. Distribution within the CNS is heterogeneous, with the largest concentrations found in basal ganglia, cerebellum, hippocampus, cerebral cortex, and nucleus accumbens. Moderate concentrations are found in the hypothalamus, amygdala, spinal cord, brain stem, central gray, and nucleus of the solitary tract. Cannabinoid receptors in the striatum are located on striatal projection neurons, and interneurons that enable functional interactions between striatal output patjways. Most, but not all, CNS cellular responses mediated by CB1 receptors are inhibitory. Lower concentrations of the CB1 receptors are present in peripheral neural and non-neural tissue.

The CB2¬ receptor is not expressed in the brain. It was originally detected in macrophages and in the marginal zone of the spleen and is particularly abundant in immune tissues. Among the formed elements of blood, the largest concentrations have been detected in B-cells and natural killer cells.

Endogenous ligands for the cannabinoid receptors discovered to date are arachidonic acid derivatives (N-arachidonylethanolamide) termed anandamide, and arachidonyl glycerol (2-AG). Most cannabinoid compounds (THC, ‘î8THC, 11-OH-‘î9THC) bind with similar affinity to CB1 and CB2, except cannabidiol which has higher affinity for CB2 receptors. Anadamide is less potent and shorter acting than THC and functions as a partial agonist in some test systems. Its distribution does not strictly parallel CB1 receptor distribution in the CNS. Arachidonyl glycerol binds with low affinity but exhibits full efficacy. In CB2-containing cells, 2-AG is a full agonist; because it functions as a partial agonist, anadamide may attenuate the activity of 2-AG in some of these cells.

Specific cannabinoid receptor agonists and antagonists for CB1¬ and CB2 receptors are available to further enhance knowledge about the functional roles of endogenous cannabinoids. Anandamide inhibits motor activity, prolactin release, and gastrointestinal motility; causes hypothermia, analgesia, hypotension, and bradycardia; interferes with learning and memory; activates the hypothalamic-pituitary-adrenal axis; decreases intraocular pressure; and modulates several immune parameters. Recently, it has been proposed that anandamide also activates the vanilloid receptor (VR1); VR1 is a ligand-gated ion channel that is activated by capsaicin, and plays an important role in modulating pain and inflammation. Cannabinoids also may exert antioxidant and cytoprotective effects that are independent of receptor activity.