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-delta9-tetrahydrocannabinol (delta9-THC), (-)-cannabidiol (CBD) and (-)-trans-delta9-tetrahydrocannabivarin (delta9-THCV), interact with cannabinoid CB1 and CB2 receptors. Delta9-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. Delta9-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. Delta9-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 delta9-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which delta9-THC, CBD and delta9-THCV interact with pharmacological targets other than CB1 or CB2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0707442

The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin

CB2 was first considered to be the ‘peripheral cannabinoid receptor’. This title was bestowed based on its abundant expression in the immune system and presumed absence from the central nervous system. However, multiple recent reports question the absence of CB2 from the central nervous system. For example, it is now well accepted that CB2 is expressed in brain microglia during neuroinflammation. However, the extent of CB2 expression in neurons has remained controversial. There have been studies claiming either extreme-its complete absence to its widespread expression-as well as everything in between. This review will discuss the reported tissue distribution of CB2 with a focus on CB2 in neurons, particularly those in the central nervous system as well as the implications of that presence. As CB2 is an attractive therapeutic target for pain management and immune system modulation without overt psychoactivity, defining the extent of its presence in neurons will have a significant impact on drug discovery. Our recommendation is to encourage cautious interpretation of data that have been presented for and against CB2's presence in neurons and to encourage continued rigorous study.

This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x

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CB2: a cannabinoid receptor with an identity crisis

Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.2008.00048.x

Emerging strategies for exploiting cannabinoid receptor agonists as medicines

http://www.medicinalgenomics.com/wp-content/uploads/2011/12/Progress-in-lipid-research.pdf

Is lipid signaling through cannabinoid 2 receptors part of a protective system

The discovery of the endocannabinoid system, comprising the G-protein coupled cannabinoid 1 and 2 receptors (CB1/2), their endogenous lipid ligands or endocannabinoids, and synthetic and metabolizing enzymes, has triggered an avalanche of experimental studies implicating the endocannabinoid system in a growing number of physiological/pathological functions. These studies have also suggested that modulating the activity of the endocannabinoid system holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders; obesity/metabolic syndrome; cachexia; chemotherapy-induced nausea and vomiting; and tissue injury and pain, amongst others. However, clinical trials with globally acting CB1 antagonists in obesity/metabolic syndrome, and other studies with peripherally-restricted CB1/2 agonists and inhibitors of the endocannabinoid metabolizing enzyme in pain, have introduced unexpected complexities, suggesting that a better understanding of the pathophysiological role of the endocannabinoid system is required to devise clinically successful treatment strategies.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/febs.12260

Modulating the endocannabinoid system in human health and disease--successes and failures.

This review gives a brief overview of the expression patterns, molecular pharmacology and physiological role of the cannabinoid 2 receptor (CB2) in pain. Particular emphasis is given to the therapeutic utility of CB2 receptor agonists. Through studies utilizing selective CB2 receptor agonists, non-selective cannabinoid agonists in conjunction with selective CB1 and CB2 receptor antagonists, or CB2 receptor knockout mice, it is now clear that this receptor plays a critical role in nociception. To this end, CB2 receptors have been shown to modulate acute pain, chronic inflammatory pain, post-surgical pain, cancer pain and pain associated with nerve injury. Here we review these studies and the compounds that were utilized. We hypothesize the mechanism of action by which the CB2 receptor could be involved in these processes. Finally we summarize the most recent novel chemical scaffolds that are being investigated towards advancing selective CB2 receptor agonists into the clinic. Many new pharmacological agents have been identified by high throughput screening and small molecule lead discovery and optimization in the past 10 years. It is anticipated that at least some of these agents may ultimately constitute effective new pain therapeutics that lack the side effects associated with traditional cannabinoid ligands.

G T. Whiteside

Papers

The role of the cannabinoid CB2 receptor in pain transmission and therapeutic potential of small molecule CB2 receptor agonists.