Pharmacological Actions of Cannabinoids 5Fig. 3.The structures of five putative endogenous cannabinoids
cium released from inositol 1,4,5-triphosphate-controlled intracellular stores in
responsetoaCB 1 receptor-mediated activation of phospholipase C. CB 2 receptors
are expressed mainly by immune cells that include lymphocytes, macrophages,
mast cells, natural killer cells, peripheral mononuclear cells and microglia (re-
viewed in Howlett et al. 2002; Pertwee 1997; see also the chapter by Cabral and
Staab,thisvolume).LessisknownabouttherolesofCB 2 than of CB 1 receptors,
although there is good evidence that CB 2 receptors can trigger microglial cell mi-
gration (Sect. 4.1.5) and regulate cytokine release. Thus, one property CB 1 and CB 2
receptors share is the ability to modulate ongoing release of chemical messengers.
The discovery of cannabinoid receptors was followed by the demonstration that
mammalian tissues can produce endogenous agonists for these receptors, all of
whichhavesofarprovedtobederivativesofarachidonicacid(reviewedinDiMarzo
et al. 1998; Hillard 2000; Mechoulam et al. 1998; see also the chapter by Di Marzo
et al., this volume). The most investigated of these “endocannabinoids” have been
arachidonoylethanolamide (anandamide) and 2-arachidonoyl glycerol (Fig. 3),
bothofwhicharesynthesizedondemandratherthanstored.Othercompoundsthat
may be endocannabinoids include 2-arachidonylglyceryl ether (noladin ether),O-
arachidonoylethanolamine (virodhamine) andN-arachidonoyldopamine (How-
lett et al. 2002; Porter et al. 2002; Walker et al. 2002). Endocannabinoids together
with cannabinoid receptors constitute what is now usually referred to as the “en-
docannabinoid system”. It is likely that endocannabinoids function as both neu-
romodulators and immunomodulators and indeed, there is already evidence that
within the central nervous system they serve as retrograde synaptic messengers