cbd oil receptors

December 15, 2021 By admin Off

It is now well established that Δ 9 -THC is a cannabinoid CB 1 and CB 2 receptor partial agonist and that depending on the expression level and coupling efficiency of these receptors it will either activate them or block their activation by other cannabinoids. Further research is now required to establish in greater detail the extent to which the in vivo pharmacology of Δ 9 -THC is shaped by these opposing actions both in healthy organisms, for example following a decrease in cannabinoid receptor density or signalling caused by prior cannabinoid administration, and in animal disease models or human disorders in which upward or downward changes in CB 1 /CB 2 receptor expression, CB 1 /CB 2 -receptor-coupling efficiency and/or in endocannabinoid release onto CB 1 or CB 2 receptors have occurred in cells or tissues that mediate unwanted effects or determine syndrome/disease progression. The extent to which the balance between cannabinoid receptor agonism and antagonism following in vivo administration of Δ 9 -THC is influenced by the conversion of this cannabinoid into the more potent cannabinoid receptor agonist, 11-OH-Δ 9 -THC, also merits investigation.

Some non-CB 1 , non-CB 2 actions of Δ 9 -THC can also be produced by certain other cannabinoid receptor agonists at concentrations of 1 μ M or less. For example, like Δ 9 -THC, both anandamide and 2-arachidonoylglycerol can activate GPR55 (Ryberg et al. , 2007) and modulate conductance in ligand-gated ion channels of glycine receptors (reviewed in Oz, 2006), and the phytocannabinoid, cannabinol, can activate putative non-CB 1 , non-CB 2 , non-transient receptor potential vanilloid receptor 1 (non-TRPV1) peripheral neuronal receptors, though 11-hydroxy-Δ 9 -THC, Δ 9 -THC-11-oic acid, HU-210 and CP55940 cannot (Zygmunt et al. , 2002). Some cannabinoids have been found to share the ability of Δ 9 -THC to reduce conductance in ligand-gated ion channels of human 5-HT 3A receptors at submicromolar concentrations (Barann et al. , 2002). Importantly, Δ 9 -THC is the most potent of these cannabinoids as an inhibitor of these ion channels, the rank order of potency being Δ 9 -THC> R -(+)-WIN55212>anandamide>(2-methyl-1-propyl-1 H -indol-3-yl)-1-naphthalenylmethanone>CP55940, and consequently quite unlike that for CB 1 or CB 2 receptor agonism. It is also known that Δ 9 -THC-like antioxidant activity is exhibited by several other phenolic cannabinoids, for example CBD ( Table 3 ) and HU-210 (reviewed in Pertwee, 2005a).

The finding that Δ 9 -THCV exhibits less potency against CP55940 or R -(+)-WIN55212 in mouse whole-brain membranes than in the vas deferens (Thomas et al. , 2005; Pertwee et al. , 2007b) indicates that it displays not only agonist dependence as an antagonist, but also tissue dependence. Further evidence for such tissue dependence was recently obtained by Dennis et al. (2007), who found that eΔ 9 -THCV antagonizes R -(+)-WIN55212-induced stimulation of [ 35 S]GTPγS binding more potently in mouse cerebellar membranes (apparent K B =7 n M ) than in mouse piriform cortical membranes (apparent K B =54 n M ). Clearly, further experiments are now required to establish why eΔ 9 -THCV does not display the same potency against CP55940 or R -(+)-WIN55212 in all CB 1 -expressing tissues and brain areas. It will also be important to investigate why, according to Schild analysis, Δ 9 -THCV appears to antagonize R -(+)-WIN55212 competitively in the mouse isolated vas deferens (Thomas et al. , 2005) but non-competitively in both mouse cerebellar and piriform cortical membranes (Dennis et al. , 2007).

The discovery that Δ 9 -THCV can antagonize cannabinoid receptor agonists was made in experiments with the mouse isolated vas deferens (Thomas et al. , 2005), a tissue in which such agonists are thought to inhibit electrically evoked contractions by acting on prejunctional neuronal CB 1 receptors to inhibit contractile transmitter release (Howlett et al. , 2002). These experiments showed eΔ 9 -THCV to behave as a competitive surmountable antagonist of CP55940 and other established cannabinoid receptor agonists at a concentration (100 n M ) at which it did not affect clonidine- or capsaicin-induced inhibition of evoked contractions of the vas deferens or produce any sign of CB 1 receptor activation or inverse agonism. Unexpectedly, the antagonism displayed by eΔ 9 -THCV in the vas deferens was found to be ligand dependent. Thus, the mean apparent K B values of eΔ 9 -THCV for its antagonism of anandamide, R -(+)-WIN55212, methanandamide, CP55940 and Δ 9 -THC were 1.2, 1.5, 4.6, 10.3 and 96.7 n M, respectively. The mean apparent K B values of eΔ 9 -THCV for its antagonism of anandamide, R -(+)-WIN55212, methanandamide and CP55940 in this tissue preparation are significantly less than the K i values of eΔ 9 -THCV for its displacement of [ 3 H]CP55940 from mouse brain membranes (Thomas et al. , 2005). So too is the apparent K B value of O-4394 against R -(+)-WIN55212 in the vas deferens (4.8 n M ) (Pertwee et al. , 2007b). The questions of why Δ 9 -THCV exhibits such potency as an antagonist of these cannabinoid receptor agonists in the vas deferens and of why it produces antagonism in this tissue that is ligand-dependent have yet to be answered.

R -(+)-WIN55212, anandamide and/or 2-arachidonoylglycerol to modulate ion currents in various voltage-gated or ligand-gated ion channels (reviewed in Oz, 2006).

Future directions.

The extent to which and precise mechanisms through which the heterogeneity of the cannabinoid CB 1 receptor population within the brain shapes the in vivo pharmacology of Δ 9 -THC and causes it to behave differently from agonists with higher CB 1 or CB 2 efficacy warrants further investigation. So too does the hypothesis that Δ 9 -THC may sometimes antagonize responses to endogenously released endocannabinoids, not least because there is evidence that such release can modulate the signs and symptoms of certain disorders and/or disease progression (reviewed in Pertwee, 2005b; Maldonado et al. , 2006). Although this modulation often seems to be protective, there is evidence that it can sometimes produce harmful effects that, for example, give rise to obesity or contribute to the rewarding effects of drugs of dependence.

Important recent findings with Δ 9 -THCV have been that it can induce both CB 1 receptor antagonism in vivo and in vitro and signs of CB 2 receptor activation in vitro at concentrations in the low nanomolar range. Further research is now required to establish whether this phytocannabinoid also behaves as a potent CB 2 receptor agonist in vivo . Thus, a medicine that blocks CB 1 receptors but activates CB 2 receptors has potential for the management of certain disorders that include chronic liver disease and also obesity when this is associated with inflammation. The bases for the ligand and tissue dependency that Δ 9 -THCV displays as an antagonist of CB 1 /CB 2 receptor agonists in vitro also warrant further research. In addition, in view of the structural similarity of Δ 9 -THCV to Δ 9 -THC, it will be important to determine the extent to which Δ 9 -THCV shares the ability of Δ 9 -THC, and indeed of CBD, to interact with pharmacological targets other than CB 1 or CB 2 receptors at concentrations in the nanomolar or low micromolar range. It will also be important to establish the extent to which CB 1 – and CB 2 -receptor-independent actions contribute to the overall in vivo pharmacology of each of these phytocannabinoids and give rise to differences between the in vivo pharmacology of Δ 9 -THC or Δ 9 -THCV and other cannabinoid receptor ligands such as CP55940, R -(+)-WIN55212 and SR141716A.

The production of tolerance by a cannabinoid receptor agonist when it is used as a medicine need not be disadvantageous since it may serve to widen the drug’s therapeutic window. Thus there is evidence first, that tolerance develops less readily to some effects of a cannabinoid receptor agonist than to others (reviewed in Pertwee, 2004a; Lichtman and Martin, 2005) and second, that some sought-after therapeutic effects of a CB 1 receptor agonist may be more resistant to tolerance development than some of its unwanted effects (De Vry et al. , 2004). Since, in mice, Δ 9 -THC can induce tolerance to some (though not all) effects of exogenously administered anandamide (Wiley et al. , 2005b), it may be that it has the capacity to render patients with certain disorders tolerant to this endocannabinoid when it is being released in a manner that is either protective or causing unwanted effects (reviewed in Pertwee, 2005b).

The structures of the phytocannabinoids, (−)-Δ 9 -tetrahydrocannabinol (Δ 9 -THC), (−)-Δ 8 -tetrahydrocannabinol (Δ 8 -THC), cannabinol, (−)-Δ 9 -tetrahydrocannabivarin (Δ 9 -THCV), (−)-cannabidiol (CBD) and cannabigerol.

Additional in vitro evidence that Δ 9 -THCV can block the activation of neuronal CB 1 receptors has come recently from experiments with murine cerebellar slices (Ma et al. , 2006). The results obtained suggest first, that eΔ 9 -THCV can block CB 1 -mediated inhibition of GABA release from basket-cell interneurons caused by R -(+)-WIN55212 and second, that by itself eΔ 9 -THCV shares the ability of the CB 1 receptor antagonist/inverse agonist, AM251, to increase GABA release from these neurons. These effects were observed at a concentration (5.8 μ M ) below any at which eΔ 9 -THCV has been found to induce signs of inverse agonism in the [ 35 S]GTPγS-binding assay when this is performed with murine cerebellar membranes (Dennis et al. , 2007). It will now be important to establish whether eΔ 9 -THCV is increasing GABA release by opposing activation of basket-cell CB 1 receptors by endogenously released endocannabinoid molecules, not least because such an effect could explain why eΔ 9 -THCV has also been found to disrupt the spread of epileptiform activity induced in rat piriform cortical slices by Mg 2+ -free Krebs medium (Weston et al. , 2006), an observation that does of course raise the possibility that Δ 9 -THCV may display anticonvulsant activity in vivo .

Finally, cannabis is a source not only of Δ 9 -THC, CBD and Δ 9 -THCV but also of at least 67 other phytocannabinoids and as such can be regarded as a natural library of unique compounds. The therapeutic potential of many of these ligands still remains largely unexplored prompting a need for further preclinical and clinical research directed at establishing whether phytocannabinoids are indeed ‘a neglected pharmacological treasure trove’ (Mechoulam, 2005). As well as leading to a more complete exploitation of Δ 9 -THC and CBD as therapeutic agents and establishing the clinical potential of Δ 9 -THCV more clearly, such research should help to identify any other phytocannabinoids that have therapeutic applications per se or that constitute either prodrugs from which semisynthetic medicines might be manufactured or lead compounds from which wholly synthetic medicines might be developed.

Moving on to experiments performed with hCB 2 -CHO cell membranes, Thomas et al. (2007) found the mean apparent K B value of CBD for antagonism of CP55940 in the [ 35 S]GTPγS-binding assay (65 n M ) to be markedly less than its K i value for displacing [ 3 H]CP55940 from these membranes ( Table 1 ). As in mouse brain membranes, so too in hCB 2 -CHO cell membranes CBD administered by itself inhibits [ 35 S]GTPγS binding (MacLennan et al. , 1998b; Thomas et al. , 2007). Since it is inhibitory in this bioassay at 1 μ M , the concentration at which it also antagonizes CP559540, it is possible that CBD produces this antagonism of CP55940 in a non-competitive manner by ‘physiologically’ opposing the ability of this agonist to stimulate CB 2 receptors. This hypothesis is supported by the findings first, that 1 μ M CBD produces a marked downward displacement of the CP55940 log concentration–response curve in the [ 35 S]GTPγS-binding assay and second, that this downward displacement appears to account entirely for this antagonism of CP55940 by CBD (Thomas et al. , 2007). Further experiments are now required to establish whether CBD also behaves as an inverse agonist in a tissue in which CB 2 receptors are expressed naturally and whether, as in brain experiments, there is any indication of an additional pharmacological target in such a tissue through which CBD can also act to produce signs of CB 2 inverse agonism. If CBD does indeed interact with more than one target to produce its inverse effect in brain tissue and/or in a tissue that expresses CB 2 receptors naturally, it will also be important to establish whether these interactions take place in an additive or synergistic manner.

Although Δ 9 -THCV seems to be capable of eliciting CB 1 -receptor-mediated responses in vivo , there is also evidence that it can behave as a CB 1 receptor antagonist both in vivo and in vitro . Thus, when administered to mice in vivo at doses below those at which it produces signs of CB 1 receptor agonism, O-4394 has been found to block effects of Δ 9 -THC that are thought to be CB 1 receptor mediated. Moreover, when administered in vitro , both O-4394 and eΔ 9 -THCV antagonize established CB 1 /CB 2 receptor agonists in a surmountable manner (Thomas et al. , 2005; Pertwee et al. , 2007b). More specifically, O-4394 has been found to attenuate Δ 9 -THC-induced hypothermia at 0.3 and 3 mg kg −1 i.v. and Δ 9 -THC-induced antinociception in the tail-flick test at 3 mg kg −1 i.v., and both O-4394 and eΔ 9 -THCV antagonize CP55940-induced stimulation of [ 35 S]GTPγS binding to mouse whole-brain membranes with mean apparent K B values (82 and 93 n M, respectively) that do not deviate significantly from their CB 1 K i values for displacement of [ 3 H]CP55940 from these membranes ( Table 1 ; Thomas et al. , 2005; Pertwee et al. , 2007b). In contrast to SR141716A and CBD (Thomas et al. , 2007), Δ 9 -THCV (O-4394) lacks detectable inverse agonist activity in the [ 35 S]GTPγS-binding assay performed with mouse whole-brain membranes and also fails to produce any detectable stimulation of [ 35 S]GTPγS binding to such membranes (Pertwee et al. , 2007b). Even so, it would be premature to conclude that Δ 9 -THCV lacks significant efficacy as a CB 1 receptor inverse or partial agonist until its actions have been investigated in other in vitro bioassays that display greater sensitivity than the [ 35 S]GTPγS-binding assay to ligands of this kind.

CP55940 and R -(+)-WIN55212 to activate central putative non-CB 1 , non-CB 2 , TRPV1-like receptors (Hájos and Freund, 2002);

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 -Δ 9 -tetrahydrocannabinol (Δ 9 -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 Δ 9 -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 Δ 9 -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 CB 1 receptor, first cloned in 1990 (Matsuda et al. , 1990), and the CB 2 receptor, cloned in 1993 (Munro et al. , 1993).

The CB 1 receptor pharmacology of Δ 9 -THCV.

Although CB 1 receptors generally mediate an inhibitory effect on any ongoing transmitter release from the neurons on which they are expressed, activation of these receptors in vivo sometimes leads to increased transmitter release from other neurons. More specifically, there is evidence that in vivo administration of Δ 9 -THC produces CB 1 -mediated increases in the release of acetylcholine in rat hippocampus, of acetylcholine, glutamate and dopamine in rat prefrontal cortex, and of dopamine in mouse and rat nucleus accumbens (Pertwee and Ross, 2002; Pistis et al. , 2002; Gardner, 2005; Nagai et al. , 2006; Pisanu et al. , 2006). At least some of these increases most probably occur because this cannabinoid is directly or indirectly inhibiting the release of an inhibitory transmitter onto acetylcholine-, glutamate- or dopamine-releasing neurons. Thus, for example, Δ 9 -THC may augment dopamine release in the nucleus accumbens by acting on CB 1 receptors to inhibit the release of glutamate onto GABAergic neurons that project from the nucleus accumbens to the ventral tegmental area where they exert an inhibitory effect on the firing of dopaminergic neurons projecting back to the nucleus accumbens (reviewed in Pertwee and Ross, 2002). Similarly, since there is evidence that acetylcholine release in the prefrontal cortex is regulated by inhibitory GABAergic neurons that project from the nucleus accumbens, it is possible that Δ 9 -THC enhances cortical acetylcholine release through a ‘disinhibitory’ process that involves a CB 1 -mediated suppression of GABA release onto cortical acetylcholine-releasing neurons (reviewed in Pertwee and Ross, 2002). It has also been proposed that it is the stimulatory effect of Δ 9 -THC on dopamine release in the nucleus accumbens that accounts for its ability to increase acetylcholine release in rat prefrontal cortex and hippocampus (Pisanu et al. , 2006). This effect on dopamine release most likely explains why Δ 9 -THC can induce signs of reward in animals, for example a decrease in the reward threshold for in vivo electrical self-stimulation of rat neural reward circuits, the preference shown by rats and mice for a chamber paired with Δ 9 -THC in the conditioned place preference paradigm, and lever pressing by squirrel monkeys for i.v. injections of Δ 9 -THC, an effect that seems to be CB 1 mediated as it can be blocked by the CB 1 -selective antagonist SR141716A (Braida et al. , 2004; Gardner, 2005; Justinova et al. , 2005). Δ 9 -THC-induced stimulation of dopamine release in the nucleus accumbens probably also accounts, at least in part, for the ability of this phytocannabinoid to increase food palatability/the incentive to eat and hence food intake (reviewed in Pertwee and Thomas, 2007).

Although Δ 9 -THCV may not be a CB 2 receptor inverse agonist, evidence has emerged recently that it is a CB 2 receptor partial agonist. This came from experiments with eΔ 9 -THCV in which the measured response used to indicate CB 2 receptor activation was inhibition of forskolin-induced stimulation of cyclic AMP production by hCB 2 -CHO cells (Gauson et al. , 2007). This is a bioassay that detects cannabinoid receptor activation with greater sensitivity than the [ 35 S]GTPγS-binding assay, probably because adenylate cyclase is located further along the cannabinoid receptor signalling cascade than G protein (reviewed in Pertwee, 1999; Howlett et al. , 2002). Additional experiments are now required to establish whether Δ 9 -THCV also activates CB 2 receptors in vivo . If it does, then it will be important to determine whether Δ 9 -THCV is effective against chronic liver diseases, there being evidence that one effective strategy for managing these disorders in the clinic may be to administer a medicine that simultaneously blocks CB 1 receptors and activates CB 2 receptors (Mallat et al. , 2007).

Like endogenously released endocannabinoids, CB 1 receptor agonists can act through neuronal presynaptic CB 1 receptors to inhibit ongoing neurotransmitter release (reviewed in Pertwee and Ross, 2002; Szabo and Schlicker, 2005). Indeed, it is generally accepted that this action gives rise to many of the CB 1 -receptor-mediated effects that Δ 9 -THC produces when it is administered in vivo . It is likely, however, that neuronal CB 1 receptors are targeted in a far less selective manner by exogenously administered Δ 9 -THC than by endocannabinoid molecules when these are released, for example during retrograde signalling (reviewed in Kreitzer, 2005; Vaughan and Christie, 2005).

Because Δ 9 -THC has relatively low cannabinoid receptor efficacy, classical pharmacology predicts that its ability to activate these receptors will be particularly influenced by the density and coupling efficiencies of these receptors. It is, for example, possible that there are some CB 1 – or CB 2 -expressing cells or tissues in which Δ 9 -THC does not share the ability of higher efficacy agonists to activate CB 1 or CB 2 receptors because the density and coupling efficiencies of these receptors are too low. These will be populations of cannabinoid receptors in which Δ 9 -THC might instead antagonize agonists that possess higher CB 1 or CB 2 efficacy when these are administered exogenously or released endogenously. It is noteworthy, therefore, that both the density and coupling efficiencies of CB 1 receptors vary widely within the brain. For example, in rat, CB 1 receptor density is much higher in substantia nigra pars reticulata, entopeduncular nucleus, globus pallidus and lateral caudate–putamen than in amygdala, thalamus, habenula, preoptic area, hypothalamus and brain stem and CB 1 coupling to G proteins is markedly more efficient in hypothalamus than in frontal cortex, cerebellum or hippocampus (reviewed in Pertwee, 1997; Childers, 2006). Moreover, CB 1 receptors in mouse hippocampus are more highly expressed by GABAergic interneurons than glutamatergic principal neurons (Monory et al. , 2006). CB 1 receptors are also distributed within the mammalian brain in a species-dependent manner. Thus for example, compared to rat brains, human brains express more CB 1 receptors in the cerebral cortex and amygdala and less in the cerebellum, a finding that may explain why motor function seems to be affected more by CB 1 receptor agonists in rats than humans (Herkenham et al. , 1990). There is also evidence that a species difference in the relative sensitivities of GABA- and glutamate-releasing neurons to CB 1 receptor agonism may explain why, following administration of the high-efficacy CB 1 receptor agonist, R -(+)-WIN55212, signs of anxiety decrease in mice but increase in rats (Haller et al. , 2007).

Turning now to CBD, an important recent finding is that this cannabinoid displays unexpectedly high potency as a CB 2 receptor antagonist and that this antagonism stems mainly from its ability to induce inverse agonism at this receptor and is, therefore, essentially non-competitive in nature. Evidence that CB 2 receptor inverse agonism can ameliorate inflammation through inhibition of immune cell migration and that CBD can potently inhibit evoked immune cell migration in the Boyden chamber raises the possibility that CBD is a lead compound from which a selective and more potent CB 2 receptor inverse agonist might be developed as a new class of anti-inflammatory agent. When exploring this possibility it will be important to establish the extent to which CBD modulates immune cell migration through other pharmacological mechanisms. There is also a need for further research directed at identifying the mechanisms by which CBD induces signs of inverse agonism not only in CB 2 -expressing cells but also in brain membranes and in the mouse isolated vas deferens.

There are several reasons for believing that one important role of the neuronal CB 1 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 CB 1 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), γ-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 CB 1 receptors to inhibit the release of neurotransmitters such as glutamate and GABA. CB 2 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).

Among the effects that Δ 9 -THC seems to produce in vivo in healthy animals by activating neuronal CB 1 receptors are several that are frequently used as measured responses in bioassays for CB 1 receptor agonists (reviewed in Howlett et al. , 2002; Pertwee, 2006). For mice, these include a ‘tetrad’ of effects, suppression of locomotor activity, hypothermia, immobility in the ring test and antinociception in the tail-flick or hot-plate test. That the production of these effects by Δ 9 -THC depends on CB 1 receptor activation is supported by findings that this is readily antagonized by the selective CB 1 receptor antagonist, N -(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H -pyrazole-3-carboxamide hydrochloride (SR141716A), that most of the tetrad effects are not produced by Δ 9 -THC in mice from which the CB 1 receptor has been genetically deleted, that Δ 9 -THC produces these effects with a potency (half-maximal effective dose=1–1.5 mg kg −1 intravenous (i.v.)) that is consistent with its CB 1 receptor affinity and that they are also produced by a wide range of other established CB 1 receptor agonists (Martin et al. , 1991; Zimmer et al. , 1999; Di Marzo et al. , 2000; Wiley et al. , 2001; Varvel et al. , 2005). It is noteworthy, however, that deletion of the CB 1 receptor from mice bred on a C57BL/6J background does not affect the ability of Δ 9 -THC to induce antinociception in the tail-flick test, though it does abolish HU-210-induced antinociception in this bioassay and also Δ 9 -THC-induced antinociception in the hot-plate test (Zimmer et al. , 1999).

Table 3.

There is evidence that like established CB 1 receptor antagonists such as SR141716A and AM251 (reviewed in Pertwee, 2005b), Δ 9 -THCV can block CB 1 -mediated effects of endogenously released endocannabinoids when administered in vivo . This evidence has come from recent experiments showing that eΔ 9 -THCV shares the ability of AM251 to reduce the food intake and body weight of non-fasted and fasted ‘non-obese’ mice when administered once (Robinson et al. , 2007) and of dietary-induced obese mice when given repeatedly over 28 days (Cawthorne et al. , 2007). It has also been found that like AM251, eΔ 9 -THCV can reduce the body fat content and plasma leptin concentration and increase the 24-h energy expenditure and thermic response to food of dietary-induced obese mice (Cawthorne et al. , 2007), the data obtained suggesting that eΔ 9 -THCV produces its antiobesity effects more by increasing energy expenditure than by reducing food intake. In addition, both eΔ 9 -THCV and AM251 have been shown to reduce the time that ‘non-obese’ mice spend close to a food hopper (Robinson et al. , 2007). These experiments were prompted by conclusive evidence that established CB 1 receptor antagonists suppress feeding and body weight in animals and humans (reviewed in Matias and Di Marzo, 2007) and by the introduction into the clinic of SR141716A (rimonabant; Acomplia, Sanofi-Aventis, Paris, France) in 2006 as an antiobesity agent. Further research is now required to determine whether Δ 9 -THCV would also be effective as a medicine for the management of obesity, and indeed for drug-dependence therapy, experiments with drug-dependent animals and human subjects having shown that CB 1 receptor blockade can reduce signs of drug dependence and the incidence of relapse after drug withdrawal (reviewed in Le Foll and Goldberg, 2005).

Some pharmacological actions of cannabidiol.

Some K i values of (−)-Δ 9 -THC and certain other phytocannabinoids for the in vitro displacement of [ 3 H]CP55940 or [ 3 H]HU-243 from CB 1 – and CB 2 -specific binding sites.

(−)- trans -Δ 9 -Tetrahydrocannabinol shares the ability of anandamide and 2-arachidonoylglycerol to activate both CB 1 and CB 2 receptors. More particularly, as discussed in greater detail elsewhere (Pertwee, 1997, 1999, 2005a; Howlett et al. , 2002; Childers, 2006), it binds to cannabinoid CB 1 and CB 2 receptors with K i values in the low nanomolar range ( Table 1 ) that indicate it to have higher affinity for these receptors than its corresponding (+)- cis (6a S , 10a S ) enantiomer ((+)-Δ 9 -THC), but lower CB 1 and CB 2 affinity than certain synthetic CB 1 /CB 2 receptor agonists, for example HU-210, CP55940 and R -(+)-WIN55212. Δ 9 -THC also exhibits lower CB 1 and CB 2 efficacy than these synthetic agonists, indicating it to be a partial agonist for both these receptor types. In contrast, the affinity of Δ 9 -THC for CB 1 and CB 2 receptors does match or exceed that of the phytocannabinoids (−)-Δ 8 -THC, Δ 9 -THCV, CBD, cannabigerol and cannabinol ( Table 1 ). It has also been found that Δ 9 -THC resembles anandamide in its CB 1 affinity, in behaving as a partial agonist at CB 1 receptors, albeit with less efficacy than anandamide, and in displaying even lower efficacy at CB 2 than at CB 1 receptors in vitro . Although 2-arachidonoylglycerol also possesses Δ 9 -THC-like CB 1 affinity, it has been found in several investigations to display higher efficacy than anandamide and hence Δ 9 -THC at both CB 1 and CB 2 receptors.

This review focuses on the cannabinoid CB 1 and CB 2 receptor pharmacology of the phytocannabinoids Δ 9 -THC, (−)-cannabidiol (CBD) and (−)- trans -Δ 9 -tetrahydrocannabivarin (Δ 9 -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.

anandamide to activate putative non-CB 1 , non-CB 2 , non-TRPV1 neuronal receptors in guinea-pig small intestine (Mang et al. , 2001);

The structure and stereochemistry of the phytocannabinoid, CBD, were first elucidated by Raphael Mechoulam in the 1960s who then went on to devise a method for its synthesis (reviewed in Pertwee, 2006). In contrast to Δ 9 -THC, CBD lacks detectable psychoactivity (reviewed in Pertwee, 2004b) and only displaces [ 3 H]CP55940 from cannabinoid CB 1 and CB 2 receptors at concentrations in the micromolar range ( Table 1 ). Since it displays such low affinity for these receptors, much pharmacological research with CBD has been directed at seeking out and characterizing CB 1 – and CB 2 -independent modes of action for this phytocannabinoid ( Table 3 ). Recently, however, evidence has emerged that in spite of its low affinity for CB 1 and CB 2 receptors, CBD can interact with these receptors at reasonably low concentrations. This has come from the discovery that CBD is capable of antagonizing cannabinoid CB 1 /CB 2 receptor agonists with apparent K B values in the low nanomolar range both in mouse whole-brain membranes and in membranes prepared from Chinese hamster ovary (CHO) cells transfected with hCB 2 receptors (Thomas et al. , 2007).

(−)- trans -Δ 9 -Tetrahydrocannabinol can also produce antagonism at the CB 2 receptor. Thus, Bayewitch et al. (1996) have found Δ 9 -THC (0.01–1 μ M ) to exhibit only marginal agonist activity in COS-7 cells transfected with human CB 2 (hCB 2 ) receptors when the measured response was inhibition of cyclic AMP production stimulated by 1 μ M forskolin. Instead, Δ 9 -THC behaved as a CB 2 receptor antagonist in this bioassay at both 0.1 and 1 μ M with an apparent K B value against HU-210 of 25.6 n M . More recently, Kishimoto et al. (2005) found that Δ 9 -THC (1 μ M ) shares the ability of the CB 2 -selective antagonist, N -[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528), to abolish 2-arachidonoylglycerol-induced migration of human leukaemic natural killer cells.

CB 1 R is prominently expressed in the central nervous system (CNS) and has drawn great attention as it participates in a variety of brain function modulations, including executive, emotional, reward, and memory processing via direct interactions with the endocannabinoid system and indirect effects on the glutamatergic, GABAergic and dopaminergic systems. Unlike CB 1 R, CB 2 R was considered as a “peripheral” cannabinoid receptor. However, this concept has been challenged recently by the identification of functional CB 2 Rs throughout the central nervous system (CNS). When compared with CB 1 R, brain CB 2 R exhibits several unique features: (1) CB 2 Rs have lower expression levels than CB 1 Rs in the CNS, suggesting that CB 2 Rs may not mediate the effects of cannabis under normal physiological conditions; (2) CB 2 Rs are dynamic and inducible; thus, under some pathological conditions (e.g., addiction, inflammation, anxiety, epilepsy etc.), CB 2 R expression can be upregulated in the brain, suggesting CB 2 R involvement in various psychiatric and neurological diseases; (3) brain CB 2 Rs are mainly expressed in neuronal somatodendritic areas (postsynaptic), while CB 1 Rs are predominantly expressed in neuronal presynaptic terminals, suggesting an opposite role of CB 1 Rs and CB 2 Rs in regulation of neuronal firing and neurotransmitter release. Based on these characteristics, CB 2 Rs have been considered to be an important substrate for neuroprotection, and targeting CB 2 Rs will likely offer a novel therapeutic strategy for treating neuropsychiatric and neurological diseases without CB 1 R-mediated side effects.

Complexity: Cannabinoid system is very complex, including many ligands (plant-derived, synthetic and endogenous), various types of targets (CB 1 R, CB 2 R, GRP55, TRPV1, and others), multi-signal pathways (ERK/MAPK and cAMP/PKA), and a lot of ion channels (Ca 2+ , K + , Cl − and TRP channels).

In this Special Issue, I have collected 7 articles that study and discuss cannabinoid receptors (3 for CB 1 R, 4 for CB 2 R). The research article “Cannabinoid CB 1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats” evaluates the potential utility of the CB 1 R neutral antagonist AM4113 in treatment of opioid abuse and addiction and compares the therapeutic anti-addictive effects and the possible side-effects of AM4113 and the classical CB 1 R antagonist/inverse agonist SR141716A in animal models of addiction. The authors found that systemic administration of AM4113 significantly inhibited intravenous heroin self-administration similar to SR141716A. However, SR141716A also exhibited aversive effect while AM4113 did not. These findings suggest that AM4113 or other neutral CB 1 R antagonists may serve as a new class of CB 1 R-based medications for the treatment of opioid addiction without SR141716A-like side-effects [5]. In the review article entitled “Translational potential of allosteric modulators targeting the cannabinoid CB 1 receptor”, the authors discuss recent advances in structural and mechanistic studies on CB 1 R allosteric modulators. They suggest that allosteric CB 1 modulators provide tremendous opportunities to develop CB 1 ligands with novel mechanisms of action; these ligands potentially improve the pharmacological effects and enhance drug safety in treating the disorders by regulating the functions of the CB 1 receptor [6]. In a research article “Identification of novel mouse and rat CB 1 R isoforms and in silico modeling of human CB 1 R for peripheral cannabinoid therapeutics”, the authors provide experimental evidence that human CB 1 R has a special isoform in peripheral but not in the CNS (called peripherally enriched CB 1 isoforms), but this feature does not exist in rodents [7]. This study challenges the experimental approach that targeting peripheral CB 1 R is desirable for the treatment of metabolic syndromes without adverse neuropsychiatric effects using rodents.

Perspectives and remarks.

In the article “Cannabidiol does not display drug abuse potential in mice behavior”, the authors report original research to show that cannabidiol (CBD), the second major component in cannabis, lacks abuse potential [1]. This work will promote more CBD-related preclinical and clinical research in medication development for the treatment of neuropsychiatric diseases including substance use disorders. The article entitled “Computational systems pharmacology analysis of cannabidiol: a combination of chemogenomics-knowledgebase network analysis and integrated with silico modeling and simulation” systemically describes the potential targets of CBD, the intracellular signaling pathways, and their associations with corresponding diseases. The authors used chemogenomics-knowledge base system and systematic network analysis of pharmacological action to generate CBD-target, target-pathway, and target-disease networks by combining both the results from the in silico analysis and the reported experimental validations [2]. The potential novel targets of CBD are discussed in “GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol”, in which the authors show that CBD is an inverse agonist for the G-protein-coupled receptors 3, 6, and 12 (GPR3, GPR6, and GPR12) [3]. These orphan receptors may act as potential new molecular targets for CBD and therefore constitute new therapeutic targets for the treatment of various neurological and psychological diseases. In a review article “Brain activity of anandamide: a rewarding bliss?” the authors provide an overview from a preclinical perspective of the current state of knowledge regarding the behavioral pharmacology of ANA, with a particular emphasis on its motivational/reinforcing properties. They also discuss how modulation of ANA levels through inhibition of enzymatic metabolic pathways could provide a basis for developing new pharmaco-therapeutic tools for the treatment of substance use disorders [4].

Specificity: The most effort in cannabinoid research field is paid for identifying the specificity of cannabinoid effects. Since the above-mentioned heterogeneity and complexity, it is somehow difficult to distinguish cannabinoid’s effects through a specific receptor (CB 1 R, CB 2 R, or CB 1 -CB 2 heterodimer), a specific signal pathway and a specific ion channel. Thus far, we still do not know the impact of this “specificity” in cannabinoid pharmacology and therapeutics. The key question, for instance, is which way is better for desired pharmacology and therapeutics: the specificity or multiple targets.

For CB 2 R studies, in the article “CB 2 receptor antibody signal specificity: correlations with the use of partial CB 2 -knockout mice and anti-rat CB 2 receptor antibodies”, authors address an important question in this research field regarding CB 2 R antibody signal specificity. Authors tested four commercial available CB 2 R antibodies in wild-type and two strains of partial CB 2 R-knockout (KO) mice. The results suggest that none of the tested four polyclonal antibodies are highly mouse CB 2 R-specific. Non-specific binding may be related to the expression of mutant or truncated CB 2 R-like proteins in those partial CB 2 -KO mice and the use of anti-rat CB 2 antibodies because the epitopes are different between rat and mouse CB 2 Rs [8]. This work provides an important caution for using CB 2 R antibodies to identify CB 2 R expression in the future study. Xia et al. intent to answer another important question in cannabinoid research field, the heterogeneity. In the research article “Heterogeneity of cannabinoid ligand-induced modulations in intracellular Ca 2+ signals of mouse pancreatic acinar cells in vitro” authors report a heterogenic effects of cannabinoid ligands on the intracellular Ca 2+ signals in mouse pancreatic acinar cells, demonstrating that cannabinoid ligands exhibit the modulations of intracellular Ca 2+ signals in a heterogenic manner through both cannabinoid receptors and non-receptor mechanisms [9]. In article “Protective effect of cannabinoid receptor 2-specific agonist GW405833 on concanavalin A-induced acute liver injury”, authors report that CB 2 R agonist GW405833 protects liver cells against acute concanavalin A-induced toxicity through the CB 2 Rs expressed in liver immune cells. The application of positron emission tomography (PET) in studying CB 2 R function is summarized in a review article “Positron emission tomography (PET) of type 2 cannabinoid receptors for detecting inflammation in the central nervous system”. Authors introduce several novels of CB 2 R radiotracers that have been developed and evaluated to quantify microglial activation. Authors also summarize the recent preclinical and clinical imaging results of CB 2 R PET tracers and discuss the prospects of CB 2 R imaging using PET [10].

Heterogeneity: We should fully realize that cannabis, cannabinoid receptors, and eCB system exhibit high heterogeneity, from genes to receptors to intracellular G-protein-coupled signal pathways and membrane ion channels. For example, the same cannabinoid ligand (e.g., WIN55, 212–2) may produce biological responses through CB receptor and non-CB receptor mechanisms, and the same CB receptors (e.g., CB 1 R) may produce different biological effects.

Cannabis sativa, is also popularly known as marijuana, has been cultivated and used for recreational and medicinal purposes for many centuries. The main psychoactive content in cannabis is Δ 9 -tetrahydrocannabinol (THC). In addition to plant cannabis sativa, there are two classes of cannabinoids—the synthetic cannabinoids (e.g., WIN55212–2) and the endogenous cannabinoids (eCB), anandamide (ANA) and 2-arachidonoylglycerol (2-AG). The biological effects of cannabinoids are mainly mediated by two members of the G-protein-coupled receptor family, cannabinoid receptors 1 (CB 1 R) and 2 (CB 2 R). The endocannabinoids, cannabinoid receptors, and the enzymes/proteins responsible for their biosynthesis, degradation, and re-updating constitute the endocannabinoid system. In recent decades, the endocannabinoid system has attracted considerable attention as a potential therapeutic target in numerous physiological conditions, such as in energy balance, appetite stimulation, blood pressure, pain modulation, embryogenesis, nausea and vomiting control, memory, learning and immune response, as well as in pathological conditions such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and multiple sclerosis.

Overall, the present special issue provides an overview and insight on pharmacological mechanisms and therapeutic potentials of cannabis, cannabinoid receptors, and eCB system. I believe that this special issue will promote further efforts to apply cannabinoid ligands as the therapeutic strategies for treating a variety of diseases. Although concepts and accumulating lines of evidence have been established, the challenges still remain in the cannabinoid research field and clinical practice. Following four aspects should be addressed in the future research regarding cannabis, cannabinoid receptors, and eCB system.

The major goal of this Special Issue is to discuss and evaluate the current progress in cannabis and cannabinoid research in order to increase our understanding about cannabinoid action and the underlying biological mechanisms and promote the development cannabinoid-based pharmacotherapies.

There are two review articles that discuss the endocannabinoid (eCB) system. The article “Integrating endocannabinoid signaling in the regulation of anxiety and depression” is focused on recent evidence that has added a new layer of complexity to the idea of targeting the eCB system for therapeutic benefits in neuropsychiatric diseases and on the future research direction of neural circuit modulations [11]. Another article “Endocannabinoid signaling in psychiatric disorders: a review of positron emission tomography studies” comprehensively reviewed PET studies examining differences in endocannabinoid signaling between individuals with psychiatric illness and healthy controls [12]. The possible cross-talk between the endocannabinoid and endovanilloid (vanilloid type 1, TRPV1) systems is discussed in the article “Developmental and behavioral effects in neonatal and adult mice following prenatal activation of endocannabinoid receptors by capsaicin”. Here the authors found that prenatal exposure to capsaicin altered plus-maze performance, and the conditioned place preference/aversion paradigm following conditioning with capsaicin in adult animals [13]. Based on available data they suggest that the interaction between the endocannabinoid and endovanilloid signaling systems can be exploited for therapeutic applications in health and disease.

Inducible profile: Cannabinoid receptor, particularly brain CB 2 R, expression displays dynamic and inducible profiles under various pathological conditions. The inducible feature makes brain CB 2 Rs possible as therapeutic targets in the treatment of diseases without interruption of normal brain function.