The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids : D9-tetrahydrocannabinol, cannabidiol and D9-tetrahydrocannabivarin
Roger G. Pertwee
British Journal of Pharmacology, 2008, 153, 199–215
doi:10.1038/sj.bjp.0707442
Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (-)-trans-D9-tetrahydrocannabinol (D9-THC), (-)- cannabidiol (CBD) and (-)-trans-D9-tetrahydrocannabivarin (D9-THCV), interact with cannabinoid CB1 and CB2 receptors. D9-THC, the main psychotropic constituent of cannabis, is a CB1 and CB2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1- and CB2-expressing cells or tissues, the manner with which it interacts with CB2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. D9-THCV behaves as a potent CB2 receptor partial agonist in vitro. In contrast, it antagonizes cannabinoid receptor agonists in CB1 expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. D9-THCV also interacts with CB1 receptors when administered in vivo, behaving either as a CB1 antagonist or, at higher doses, as a CB1 receptor agonist. Brief mention is also made in this review, first of the production by D9-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which D9-THC, CBD and D9-THCV interact with pharmacological targets other than CB1 or CB2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.
Keywords : cannabis; D9-tetrahydrocannabinol; cannabidiol; D9-tetrahydrocannabivarin; CB1 receptors; CB2 receptors; cannabinoid receptor agonism; cannabinoid receptor antagonism; clinical applications; endocannabinoid system
Introduction
It was research in the 1960s and early 1970s that led to the discovery that the psychotropic effects of cannabis are produced mainly by (-)-trans-D9-tetrahydrocannabinol (D9- THC; Figure 1), to the pharmacological characterization of this plant cannabinoid (phytocannabinoid) and to the development of synthetic cannabinoids (reviewed in Pertwee, 2006). These advances led on to the introduction into the clinic in the 1980s of D9-THC (dronabinol, Marinol, Solvay Pharmaceuticals, Brussels, Belgium) and of one of its synthetic analogues, nabilone (Cesamet, Valeant Pharmaceuticals, Aliso Viejo, CA, USA), for the suppression of nausea and vomiting produced by chemotherapy and, in 1992, of Marinol for the stimulation of appetite in AIDS patients (reviewed in Robson, 2005; Pertwee and Thomas, 2007). Importantly, they also led on to the discovery that many of the effects produced by D9-THC and its synthetic cousins depend on the ability of these ligands to target a new family of receptors (reviewed in Howlett et al., 2002; Pertwee, 2005a, 2006). Two types of these cannabinoid receptors have so far been identified and both are members of the superfamily of G-protein-coupled receptors. These are the CB1 receptor, first cloned in 1990 (Matsuda et al., 1990), and the CB2 receptor, cloned in 1993 (Munro et al., 1993).
The cloning of the CB1 receptor was soon followed by the discovery that mammalian tissues can produce compounds that activate this receptor, and subsequently by the characterization of ligands such as D9-THC, (6aR)-trans-3-(1, 1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl- 6H-dibenzo[b,d]pyran-9-methanol (HU-210), (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-
(3-hydroxypropyl) cyclohexanol (CP55940) and (R)-(þ)-[2,3- dihydro-5-methyl-3-(4 morpholinyl-methyl) pyrrolo-[1,2,3-de]-1, 4-benzoxazin-6-yl]-1-naphthalenylmethanone (R-( þ)- WIN55212) as mixed CB1/CB2 receptor agonists and by the development of CB1- and CB2-selective agonists and antagonists (reviewed in Howlett et al., 2002; Pertwee, 2005a, 2006). It also soon became clear that CB1 receptors are located primarily in central and peripheral neurons and CB2 receptors predominantly in immune cells. CB1 receptors are also expressed by some non-neuronal cells, including immune cells, and CB2 receptors by some neurons both within and outside the brain (Skaper et al., 1996; Ross et al., 2001; Van Sickle et al., 2005; Wotherspoon et al., 2005; Beltramo et al., 2006; Gong et al., 2006). However, the role of neuronal CB2 receptors is currently unknown. The first endogenous cannabinoid receptor agonists (endocannabinoids) to be identified were N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (Devane et al., 1992; Mechoulam et al., 1995; Sugiura et al., 1995), each of which can activate both CB1 and CB2 receptors and is synthesized on demand in response to elevations of intracellular calcium (Howlett et al., 2002; Di Marzo et al., 2005). Together with their receptors, these and other more recently discovered endocannabinoids (Pertwee, 2005b) constitute what is now usually referred to as the ‘endocannabinoid system’.
There are several reasons for believing that one important role of the neuronal CB1 component of the endocannabinoid system is to modulate neurotransmitter release in a manner that maintains homeostasis in health and disease by preventing the development of excessive neuronal activity in the central nervous system. First, neuronal CB1 receptors are found mainly at the terminals of central and peripheral neurons. Second, there is good evidence that these receptors can mediate inhibition of ongoing release of a number of different excitatory and inhibitory transmitters, for example acetylcholine, noradrenaline, dopamine, 5-hydroxytryptamine (5-HT), g-aminobutyric acid (GABA), glutamate, D-aspartate and cholecystokinin (Howlett et al., 2002; Pertwee and Ross, 2002; Szabo and Schlicker, 2005). Finally, there is convincing evidence that endocannabinoids serve as retrograde synaptic messengers (Kreitzer, 2005; Vaughan and Christie, 2005). Thus, it is now generally accepted that postsynaptic increases in intracellular calcium induced by certain neurotransmitters can trigger the biosynthesis and release into the synapse of endocannabinoid molecules, which then act on presynaptic CB1 receptors to inhibit the release of neurotransmitters such as glutamate and GABA. CB2 receptor activation can also alter the release of chemical messengers, in this case the release of cytokines from
immune cells and may, in addition, affect immune function by modulating immune cell migration both within and outside the central nervous system (reviewed in Walter and Stella, 2004; Cabral and Staab, 2005; Pertwee, 2005a).
This review focuses on the cannabinoid CB1 and CB2 receptor pharmacology of the phytocannabinoids D9-THC, (-)-cannabidiol (CBD) and (-)-trans-D9-tetrahydrocannabivarin (D9-THCV) (Figure 1), all three of which interact with these receptors at reasonably low concentrations. Whenever possible, previous review articles have been cited that provide more detailed information and list additional references.
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