Background and purpose: A nonpsychoactive constituent of the cannabis plant, cannabidiol has been demonstrated to have low affinity for both cannabinoid CB1 and CB2 receptors. We have shown previously that cannabidiol can enhance electrically evoked contractions of the mouse vas deferens, suggestive of inverse agonism. We have also shown that cannabidiol can antagonize cannabinoid receptor agonists in this tissue with a greater potency than we would expect from its poor affinity for cannabinoid receptors. This study aimed to investigate whether these properties of cannabidiol extend to CB1 receptors expressed in mouse brain and to human CB2 receptors that have been transfected into CHO cells.
Experimental approach: The [35S]GTPS binding assay was used to determine both the efficacy of cannabidiol and the ability of cannabidiol to antagonize cannabinoid receptor agonists (CP55940 and R-(+)-WIN55212) at the mouse CB1 and the human CB2 receptor.
Key results: This paper reports firstly that cannabidiol displays inverse agonism at the human CB2 receptor. Secondly, we demonstrate that cannabidiol is a high potency antagonist of cannabinoid receptor agonists in mouse brain and in membranes from CHO cells transfected with human CB2 receptors.
Conclusions and implications: This study has provided the first evidence that cannabidiol can display CB2 receptor inverse agonism, an action that appears to be responsible for its antagonism of CP55940 at the human CB2 receptor. The ability of cannabidiol to behave as a CB2 receptor inverse agonist may contribute to its documented anti-inflammatory properties.
There is evidence that in addition to eliciting responses in healthy animals, cannabinoid receptor activation by Δ 9 -THC can also ameliorate clinical signs or delay syndrome progression in animal models of certain disorders (reviewed in Pertwee, 2005b, 2007a; Pertwee and Thomas, 2007). This it does in a manner that not only supports the established clinical applications of Δ 9 -THC and nabilone for appetite stimulation and antiemesis and of the Δ 9 -THC- and CBD-containing medicine, Sativex (GW Pharmaceuticals, Salisbury, Wiltshire, UK), for the symptomatic relief of neuropathic pain in patients with multiple sclerosis and of cancer pain, but has also identified potential additional therapeutic uses for Δ 9 -THC, nabilone or other cannabinoid receptor agonists ( Table 2 ). Clinical evidence supporting the introduction of Δ 9 -THC or other cannabinoid receptor agonists into the clinic, for example for the management of disorders such as glaucoma and cancer, and for the relief of postoperative pain, spasms and spasticity caused by multiple sclerosis and painful spasticity triggered by spinal cord injury has also been obtained (Tomida et al., 2004, 2006; Robson, 2005; Guzmán et al., 2006; Pertwee, 2007a; Pertwee and Thomas, 2007).
anandamide to activate putative non-CB1, non-CB2, non-TRPV1 neuronal receptors in guinea-pig small intestine (Mang et al., 2001);
Non-CB1, non-CB2 pharmacological targets for Δ 9 -THC, CBD and Δ 9 -THCV
Although there is no doubt that Δ 9 -THC and CBD can target both CB1 and CB2 receptors, there is also general agreement that they have a number of additional pharmacological actions ( Tables 3 and and4). 4 ). These include several actions that can be elicited by these cannabinoids at submicromolar concentrations and are, therefore, expected to reduce the selectivity of these compounds as CB1 and CB2 receptor ligands. One finding of particular interest is that the orphan receptor, GPR55 is activated by Δ 9 -THC and blocked by CBD ( Tables 3 and and4). 4 ). It will now be important to seek out effects that are mediated by GPR55 in both health and disease and to identify any potential therapeutic benefits of activating or blocking this receptor with Δ 9 -THC, CBD or other ligands. The extent to which Δ 9 -THCV can induce CB1– and CB2-receptor-independent effects remains to be established.