The Endocannabinoid System and Alcohol Dependence: Will Cannabinoid Receptor 2 Agonism be More Fruitful than Cannabinoid Receptor 1 Antagonism?

: Alcohol-use disorder (AUD) remains a major public health concern. In recent years, there has been a heightened interest in components of the endocannabinoid system for the treatment of AUD. Cannabinoid type 1 (CB1) receptors have been shown to modulate the rewarding effects of alcohol, reduce the abuse-related effects of alcohol, improve cognition, exhibit anti-inflammatory, and neuroprotective effects, which are all favorable properties of potential therapeutic candidates for the treatment of AUD. However, CB1 agonists have not been investigated for the treatment of AUD because they stimulate the motivational properties of alcohol, increase alcohol intake, and have the tendency to be abused. Preclinical data suggest significant potential for the use of CB1 antagonists to treat AUD; however, a clinical phase I/II trial with SR14716A (rimonabant), a CB1 receptor antagonist/inverse agonist showed that it produced serious neuropsychiatric adverse events such as anxiety, depression, and even suicidal ideation. This has redirected the field to focus on alternative components of the endocannabinoid system, including cannabinoid type 2 (CB2) receptor agonists as a potential therapeutic target for AUD. CB2 receptor agonists are of particular interest because they can modulate the reward pathway, reduce abuse-related effects of alcohol, reverse neuroinflammation, improve cognition, and exhibit anti-inflammatory and neuroprotective effects, without exhibiting the psychiatric side effects seen with CB1 antagonists. Accordingly, this article presents an overview of the studies reported in the literature that have investigated CB2 receptor agonists with regards to AUD and provides commentary as to whether this receptor is a worthy target for continued investigation.

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Inverse Agonism of Cannabinoid Receptor Type 2 Confers Anti-inflammatory and Neuroprotective Effects Following Status Epileptics

Molecular Neurobiology ◽

10.1007/s12035-020-01923-4 ◽

2020 ◽

Vol 57 (6) ◽

pp. 2830-2845 ◽

Cited By ~ 4

Author(s):

Ying Yu ◽

Lexiao Li ◽

Davis T. Nguyen ◽

Suni M. Mustafa ◽

Bob M. Moore ◽

...

Keyword(s):

Cannabinoid Receptor ◽

Receptor Type ◽

Neuroprotective Effects ◽

Inverse Agonism ◽

Cannabinoid Receptor Type 2 ◽

Anti Inflammatory

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Cannabinoid Receptor CB2 Is Involved in Tetrahydrocannabinol-Induced Anti-Inflammation against Lipopolysaccharide in MG-63 Cells

Mediators of Inflammation ◽

10.1155/2015/362126 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Lei Yang ◽

Fei-Fei Li ◽

Yu-Chen Han ◽

Bin Jia ◽

Yin Ding

Keyword(s):

Cannabinoid Receptor ◽

Osteosarcoma Cell ◽

Nuclear Factor ◽

Therapeutic Action ◽

Cb2 Receptor ◽

Cb1 Antagonist ◽

Anti Inflammatory ◽

Anti Inflammation ◽

Necrosis Factor ◽

Proinflammatory Factors

Cannabinoid Δ9-tetrahydrocannabinol (THC) is effective in treating osteoarthritis (OA), and the mechanism, however, is still elusive. Activation of cannabinoid receptor CB2 reduces inflammation; whether the activation CB2 is involved in THC-induced therapeutic action for OA is still unknown. Cofilin-1 is a cytoskeleton protein, participating in the inflammation of OA. In this study, MG-63 cells, an osteosarcoma cell-line, were exposed to lipopolysaccharide (LPS) to mimic the inflammation of OA. We hypothesized that the activation of CB2 is involved in THC-induced anti-inflammation in the MG-63 cells exposed to LPS, and the anti-inflammation is mediated by cofilin-1. We found that THC suppressed the release of proinflammatory factors, including tumor necrosis factorα(TNF-α), interleukin- (IL-) 1β, IL-6, and IL-8, decreased nuclear factor-κB (NF-κB) expression, and inhibited the upregulation of cofilin-1 protein in the LPS-stimulated MG-63 cells. However, administration of CB2 receptor antagonist or the CB2-siRNA, not CB1 antagonist AM251, partially abolished the THC-induced anti-inflammatory effects above. In addition, overexpression of cofilin-1 significantly reversed the THC-induced anti-inflammatory effects in MG-63 cells. These results suggested that CB2 is involved in the THC-induced anti-inflammation in LPS-stimulated MG-63 cells, and the anti-inflammation may be mediated by cofilin-1.

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2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a New Class of Cannabinoid Receptor Agonists. Part 1. Discovery of CB2 Receptor Selective Compounds.

ChemInform ◽

10.1002/chin.200746210 ◽

2007 ◽

Vol 38 (46) ◽

Author(s):

Hiroyuki Kai ◽

et al. et al.

Keyword(s):

Cannabinoid Receptor ◽

Cb2 Receptor ◽

Receptor Agonists ◽

New Class

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The Cannabinoid Agonist WIN55,212-2 Suppresses Opioid-induced Emesis in Ferrets

Anesthesiology ◽

10.1097/00000542-200105000-00029 ◽

2001 ◽

Vol 94 (5) ◽

pp. 882-887 ◽

Cited By ~ 75

Author(s):

Isabelle I. Simoneau ◽

Maged S. Hamza ◽

Heriberto P. Mata ◽

Erin M. Siegel ◽

Todd W. Vanderah ◽

...

Keyword(s):

Receptor Agonist ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Cb1 Receptors ◽

Cb2 Receptor ◽

Selective Antagonist ◽

Receptor Agonists ◽

Antiemetic Activity ◽

The Central Nervous System ◽

Cannabinoid Agonist

Background Cannabinoid receptor agonists reverse nausea and vomiting produced by chemotherapy and radiation therapy in animals and humans but have not been tested against opioid-induced emesis. This study tests the hypothesis that cannabinoid receptor agonists will prevent opioid-induced vomiting. Methods Twelve male ferrets were used. They weighed 1.2-1.6 kg at the beginning and 1.8-2.3 kg at the end of the experiments. All drugs were injected subcutaneously. WIN55,212-2, a mixed CB1-CB2 cannabinoid receptor agonist, was administered 25 min before morphine. Retches and vomits were counted at 5-min intervals for 30 min after morphine injection. Results Retching and vomiting responses increased with increasing morphine doses up to 1.0 mg/kg, above which the responses decreased. Previous administration of naloxone prevented morphine-induced retching and vomiting. WIN55,212-2 dose-dependently reduced retching and vomiting. The ED50 was 0.05 mg/kg for retches and 0.03 mg/kg for vomits. At 0.13 mg/kg, retching decreased by 76% and vomiting by 92%. AM251, a CB1 receptor-selective antagonist, blocked the antiemetic actions of WIN55,212-2, but AM630, a CB2 receptor-selective antagonist, did not. Conclusions These results demonstrate that WIN55,212-2 prevents opioid-induced vomiting and suggest that the antiemetic activity of WIN55,212-2 occurs at CB1 receptors. This is consistent with findings that CB1 receptors are the predominant cannabinoid receptors in the central nervous system and that antiemetic effects of cannabinoids appear to be centrally mediated.

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Detailed characterization of the endocannabinoid system in human macrophages and foam cells, and anti-inflammatory role of type-2 cannabinoid receptor

Atherosclerosis ◽

10.1016/j.atherosclerosis.2013.12.042 ◽

2014 ◽

Vol 233 (1) ◽

pp. 55-63 ◽

Cited By ~ 40

Author(s):

Valerio Chiurchiù ◽

Mirko Lanuti ◽

Giuseppina Catanzaro ◽

Filomena Fezza ◽

Cinzia Rapino ◽

...

Keyword(s):

Cannabinoid Receptor ◽

Endocannabinoid System ◽

Foam Cells ◽

Detailed Characterization ◽

Human Macrophages ◽

Anti Inflammatory

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Prospects for the Use of Cannabinoid Receptor Ligands for the Treatment of Metabolic Syndrome and Atherosclerosis: Analysis of Experimental and Clinical Data

Annals of the Russian academy of medical sciences ◽

10.15690/vramn779 ◽

2017 ◽

Vol 72 (1) ◽

pp. 59-65 ◽

Cited By ~ 6

Author(s):

L. N. Maslov ◽

R. S. Karpov

Keyword(s):

Metabolic Syndrome ◽

Cannabinoid Receptor ◽

Glycosylated Hemoglobin ◽

Experimental Studies ◽

Blood Lipid ◽

Cb1 Receptors ◽

Cb2 Receptor ◽

Receptor Agonists ◽

Antiatherogenic Effect ◽

Patients With Diabetes

An antagonist of central cannabinoid CB1 receptors rimonabant causes weight loss in patients with obesity and metabolic syndrome, improves blood lipid parameters, increases the adiponectin level, decreases the rate of glucose and glycosylated hemoglobin in patients with diabetes mellitustype-2. However, rimonabant adverse effects include depression, anxiety, nausea, and dizziness which are apparently due to the blockade of central CB1 receptors. In mice with a high-calorie diet, we defined that the blockade of peripheral CB1 receptors prevents obesity, steatosis of the liver, improves lipid and carbohydrate metabolism. Experimental studies suggest that peripheral CB2 receptor agonists have antiatherogenic effect. To validate the expediency of clinical research of CB2 receptor agonists in patients with atherosclerosis the comparative analysis of antiatherogenic properties of cannabinoids should be performed. In addition, experiments are needed on the combination use of cannabinoids with well-known antiatherogenic agents, such as statins.

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Neuroprotection Following Concussion: The Potential Role for Cannabidiol

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2020.23 ◽

2020 ◽

Vol 47 (3) ◽

pp. 289-300

Author(s):

Jyotpal Singh ◽

John Patrick Neary

Keyword(s):

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Endocannabinoid System ◽

Cognitive Capacity ◽

Cardiovascular Physiology ◽

Neuroprotective Effects ◽

Double Blind ◽

Apparent Lack ◽

Post Concussion Syndrome ◽

Negative Side Effects

ABSTRACT:Cannabidiol (CBD) has been generating increasing interest in medicine due to its therapeutic properties and an apparent lack of negative side effects. Research has suggested that high dosages of CBD can be taken acutely and chronically with little to no risk. This review focuses on the neuroprotective effects of a CBD, with an emphasis on its implications for recovering from a mild traumatic brain injury (TBI) or concussion. CBD has been shown to influence the endocannabinoid system, both by affecting cannabinoid receptors and other receptors involved in the endocannabinoid system such as vanilloid receptor 1, adenosine receptors, and 5-hydroxytryptamine via cannabinoid receptor-independent mechanisms. Concussions can result in many physiological consequences, potentially resulting in post-concussion syndrome. While impairments in cerebrovascular and cardiovascular physiology following concussion have been shown, there is unfortunately still no single treatment available to enhance recovery. CBD has been shown to influence the blood brain barrier, brain-derived neurotrophic factors, cognitive capacity, the cerebrovasculature, cardiovascular physiology, and neurogenesis, all of which have been shown to be altered by concussion. CBD can therefore potentially provide treatment to enhance neuroprotection by reducing inflammation, regulating cerebral blood flow, enhancing neurogenesis, and protecting the brain against reactive oxygen species. Double-blind randomized controlled trials are still required to validate the use of CBD as medication following mild TBIs, such as concussion.

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2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 1: Discovery of CB2 receptor selective compounds

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2007.04.093 ◽

2007 ◽

Vol 17 (14) ◽

pp. 4030-4034 ◽

Cited By ~ 23

Author(s):

Hiroyuki Kai ◽

Yasuhide Morioka ◽

Takami Murashi ◽

Koichi Morita ◽

Satomi Shinonome ◽

...

Keyword(s):

Cannabinoid Receptor ◽

Cb2 Receptor ◽

Receptor Agonists ◽

New Class

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Omega-3 Endocannabinoid-Epoxides Are Novel Anti-inflammatory and Anti-Pain Lipid Metabolites (FS15-01-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.fs15-01-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Cited By ~ 3

Author(s):

Aditi Das ◽

Josephine Watson ◽

Lauren Carnevale ◽

William Arnold

Keyword(s):

Fatty Acids ◽

Heart Association ◽

The Body ◽

Enzymatic Oxidation ◽

Enzymatic Reactions ◽

Cb2 Receptor ◽

Omega 3 ◽

Receptor Agonists ◽

Anti Inflammatory

Abstract Objectives Omega-3 fatty acid derived endocannabinoids are metabolized by cytochrome P450s to form bioactive endocannabinoid epoxides that are anti-inflammatory Methods Lipidomics, LC-MS/MS, microglial cells culture, lipid synthesis, extractions, enzymology Results Cannabinoids are found in marijuana and also are produced naturally in the body from ω-3 and ω-6 fatty acids. Exocannabinoids in marijuana, are known to be responsible for some of its euphoric effects, but they also exhibit anti-inflammatory benefits. Our study revealed a cascade of enzymatic reactions that convert ω-3 fatty acids into anti-inflammatory endocannabinoid epoxides that act through the same receptors in the body as marijuana (PNAS 2017). Endocannabinoids are ligands for cannabinoid receptor 1 and 2 (CB1 and CB2). CB1 receptor agonists exhibit psychotropic properties while CB2 receptor agonists have anti-inflammatory effects. Consequently, there is a strong interest in the discovery of CB2 selective agonists to mitigate inflammatory pathologies. The work details the discovery and characterization of naturally occurring ω-3–derived endocannabinoid epoxides that are formed via enzymatic oxidation of ω-3 endocannabinoids by cytochrome P450 epoxygenases. These dual functional ω-3 endocannabinoid epoxides exhibit preference towards binding to CB2 receptor and are anti-inflammatory and vasodilatory and reciprocally modulate platelet aggregation. Some of the other regioisomers of ω-3 endocannabinoid epoxides are partial agonists of CB1 and stop tumor cell metastasis (J. Med. Chem 2018). By virtue of their physiological properties, they are expected to play important roles in neuroinflammation and pain. Conclusions This finding demonstrates how omega-3 fatty acids can produce some of the same medicinal qualities as marijuana, but without a psychotropic effect. In summary, the ω-3 endocannabinoid epoxides are found at concentrations comparable to those of other endocannabinoids and are expected to play critical roles during inflammation in vivo Funding Sources American Heart Association Scientist Development award, National Institute of Health (NIH) R01, NIH R03, USDA, National Multiple Sclerosis Society.

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