ABSTRACT
Research on the mechanism of action of the psychoactive components of Cannabis sativa, the cannabinoids, culminated in the early 1990s with the finding of cannabinoid receptors and of their possible endogenous agonists (see Matsuda 1997 and Di Marzo 1998 for reviews) (Figure 10.1). These molecules, together with the proteins that regulate their activity and/or levels, constitute the “endocannabinoid system.” The first subtype of cannabinoid receptors, named CB1, is widely distributed in both nervous and non-nervous tissues, and is responsible for most of the central actions, and also for some of the peripheral ones, of plant and synthetic cannabinoids. The second subtype of cannabinoid receptors, named CB2, has been found to date in high levels only in immune tissues and cells and may mediate some of the immune-modulatory effects of the cannabinoids, although little direct evidence for this possibility has been found so far. Evidence for CB2-like receptors in peripheral nerves has been also described (Griffin et al. 1997). The finding of selective CB1 and, more recently, CB2 receptor antagonists (Rinaldi-Carmona et al. 1994, 1998; Felder et al. 1998), and the development of cannabinoid receptor knockout mice (Ledent et al. 1999; Zimmer et al. 1999; Buckley et al., 1999) will soon provide a definitive answer as to which of the typical pharmacological actions of cannabinoids are mediated by either receptor subtype, and may even support the hypothetical presence of further molecular targets for these compounds. As to the possible endogenous counterparts of the cannabinoids, over the last seven years several fatty acid derivatives have been found to mimic the properties of Δ9-tetrahydrocannabinol (THC), cannabis’s major psychoactive principle. Not all of these substances, however, have the capability to displace high affinity cannabinoid ligands from selective binding sites in membrane preparations containing the CB1 or the CB2 receptor. Anandamide (Devane et al. 1992), the amide of arachidonic acid with ethanolamine, was the first of such compounds to be isolated and received its name from the Sanskrit word for “internal bliss,” ananda. Next came two polyunsaturated congeners of anandamide (Hanus et al. 1993), and a glycerol ester, 2-arachidonoyl glycerol (2-AG) (Mechoulam et al. 1995; Sugiura et al. 1995). These compounds share the ability to bind to and activate CB1 and (particularly in the case of 2-AG) CB2 receptors. Therefore, they induce a series of pharmacological effects in vitro and in vivo that are, to some extent, similar to those exerted by THC (Hillard and Campbell 1997; Di Marzo 1998; Mechoulam et al. 1998). Hence the name “endocannabinoids” was proposed for anandamide and 2-AG. Other fatty acid derivatives (Figure 10.1), such as palmitoylethanolamide and cis-9-octadecenoamide (oleamide), do not have high affinity for either of the two cannabinoid receptor subtypes discovered so far, and yet they exhibit pharmacological actions that in some cases are cannabis-like (see Lambert and Di Marzo 1999 for review). The molecular mode of action of these latter compounds that cannot be referred to as endocannabinoids, is currently being debated and is possibly due in part to the modulation of either the action or the metabolism of anandamide and 2-AG (Mechoulam et al. 1997; Lambert and Di Marzo 1999). Chemical structures and likely molecular targets of the endocannabinoids and other cannabimimetic fatty acid derivatives. https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9780203820803/946ca563-95be-452a-a87f-573ff13484ab/content/fig10_1_B.tif" xmlns:xlink="https://www.w3.org/1999/xlink"/>
