ABSTRACT
Although ∆9(-)-tetrahydrocannabinol (THC) is not naturally found in the body, receptors for this compound in the brain have been described since 1988 (Devane et al., 1988). These receptors were later named cannabinoid 1 (CB1), and a receptor subtype (CB2) has been found in immune tissues (Munro et al., 1993). An endogenous ligand for these receptors has more recently been discovered: It is the N-ethanolamine form of arachidonic acid and was named anandamide from the Sanskrit word ananda, which means “bliss”. When anandamide [20:4n6 N-acylethanolamine (20:4n6 NAE)] was injected into animals, hypomobility, hypothermia, analgesia, and catalepsy were observed (Fride and Mechoulam, 1993). These are the classic behavioral effects of THC administration. Since this discovery, other endogenous metabolites that have been shown to be functional agonists of these receptors have been described: several polyunsaturated fatty acid derivatives, some of which are 22:6n3 NAE, 20:4n3 NAE, 20:3n6 NAE (Barg et al., 1995), 20:3n9 NAE (Pillar et al., 1995), and 2-arachidonoylglycerol (2-AG) (Mechoulam et al., 1995; Sugiura et al., 1995) (Fig. 1). These compounds are collectively termed endocannabinoids and have been shown to bind to brain CB receptors with an IC50 value equal to or 1.5-fold that of 20:4n6 NAE (Felder et al., 1995; Hillard and Campbell, 1997). The presence of CB receptors in diverse invertebrates evidences that the CB signaling system has been conserved for at least 500 million years (Stefano et al., 1996; De Petrocellis et al., 1999).
