“Despite the fact that the cannabinoid receptor type 1 (CB1R) plays a pivotal role in emotional memory processing in different regions of the brain, its function in the retrosplenial cortex (RSC) remains unknown. Here, using contextual fear conditioning in rats, we showed that a post-training intra-RSC infusion of the CB1R antagonist AM251 impaired, and the agonist CP55940 improved, long-term memory consolidation. Additionally, a post-reactivation infusion of AM251 enhanced memory reconsolidation, while CP55940 had the opposite effect. Finally, AM251 blocked extinction, whereas CP55940 facilitated it and maintained memory extinguished over time. Altogether, our data strongly suggest that the cannabinoid system of the RSC modulates emotional memory.”
Tag Archives: agonists
Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex.
“Cannabinoid (CB) agonists suppress nausea in humans and animal models; yet, their underlying neural substrates remain largely unknown.
Evidence suggests that the visceral insular cortex (VIC) plays a critical role in nausea. Given the expression of CB1 receptors and the presence of endocannabinoids in this brain region, we hypothesized that the VIC endocannabinoid system regulates nausea…
Taken together, these findings provide compelling evidence that acute nausea selectively increases 2-AG in the VIC, and suggests that 2-AG signaling within the VIC regulates nausea by reducing neuronal activity in this forebrain region.”
Cannabinoid WIN55, 212-2 induces cell cycle arrest and inhibits the proliferation and migration of human BEL7402 hepatocellular carcinoma cells.
“Hepatocellular carcinoma (HCC) is the leading cause of cancer-associated mortality worldwide; however, only limited therapeutic treatments are currently available.
The present study aimed to investigate the effects of cannabinoids as novel therapeutic targets in HCC…
These results suggested that cannabinoid receptor agonists, including WIN, may be considered as novel therapeutics for the treatment of HCC.”
http://www.ncbi.nlm.nih.gov/pubmed/26500101
http://www.thctotalhealthcare.com/category/hepatocellular-carcinoma-hcc/
Controlled downregulation of the cannabinoid CB1 receptor provides a promising approach for the treatment of obesity and obesity-derived type 2 diabetes.
“Increased activity of the endocannabinoid system has emerged as a pathogenic factor in visceral obesity, which is a risk factor for type 2 diabetes mellitus (T2DM).
The endocannabinoid system is composed of at least two G-protein-coupled receptors (GPCRs), the cannabinoid receptor type 1 (CB1), and the cannabinoid receptor type 2 (CB2).
Downregulation of CB1 activity in rodents and humans has proven efficacious to reduce food intake, abdominal adiposity, fasting glucose levels, and cardiometabolic risk factors.
Unfortunately, downregulation of CB1 activity by universally active CB1 inverse agonists has been found to elicit psychiatric side effects, which led to the termination of using globally active CB1 inverse agonists to treat diet-induced obesity.
Interestingly, preclinical studies have shown that downregulation of CB1 activity by CB1 neutral antagonists or peripherally restricted CB1 inverse agonists provided similar anorectic effects and metabolic benefits without psychiatric side effects seen in globally active CB1 inverse agonists.
Furthermore, downregulation of CB1 activity may ease endoplasmic reticulum and mitochondrial stress which are contributors to obesity-induced insulin resistance and type 2 diabetes.
This suggests new approaches for cannabinoid-based therapy in the management of obesity and obesity-related metabolic disorders including type 2 diabetes.”
Prospects for Creation of Cardioprotective Drugs Based on Cannabinoid Receptor Agonists.
“Cannabinoids can mimic the infarct-reducing effect of early ischemic preconditioning, delayed ischemic preconditioning, and ischemic postconditioning against myocardial ischemia/reperfusion. They do this primarily through both CB1 and CB2 receptors.
Cannabinoids are also involved in remote preconditioning of the heart.
The cannabinoid receptor ligands also exhibit an antiapoptotic effect during ischemia/reperfusion of the heart.
The acute cardioprotective effect of cannabinoids is mediated by activation of protein kinase C, extracellular signal-regulated kinase, and p38 kinase.
The delayed cardioprotective effect of cannabinoid anandamide is mediated via stimulation of phosphatidylinositol-3-kinase-Akt signaling pathway and enhancement of heat shock protein 72 expression.
The delayed cardioprotective effect of another cannabinoid, Δ9-tetrahydrocannabinol, is associated with augmentation of nitric oxide (NO) synthase expression, but data on the involvement of NO synthase in the acute cardioprotective effect of cannabinoids are contradictory.
The adenosine triphosphate-sensitive K+ channel is involved in the synthetic cannabinoid HU-210-induced cardiac resistance to ischemia/reperfusion injury.
Cannabinoids inhibit Na+/Ca2+ exchange via peripheral cannabinoid receptor (CB2) activation that may also be related to the antiapoptotic and cardioprotective effects of cannabinoids.
The cannabinoid receptor agonists should be considered as prospective group of compounds for creation of drugs that are able to protect the heart against ischemia-reperfusion injury in the clinical setting.”
Type 1 cannabinoid receptor modulates water deprivation-induced homeostatic responses.
“The present study investigated the type 1 cannabinoid receptor (CB1R) as a potential candidate to mediate the homeostatic responses triggered by 24 hours of water deprivation (WD), which constitutes primarily a hydroelectrolytic challenge and also significantly impacts energy homeostasis.
The present results demonstrated for the first time that CB1R mRNA expression is increased in the hypothalamus of WD rats. Furthermore, the administration of ACEA, a CB1R selective agonist, potentiated WD-induced dipsogenic effect, whereas AM251, a CB1R antagonist, attenuated not only water but also salt intake in response to WD. In parallel with the modulation of thirst and salt appetite, we confirmed that CB1Rs are essential for the development of appropriated neuroendocrine responses…
In conclusion, the present study demonstrated that CB1Rs participate in the homeostatic responses regulating fluid balance and energy homeostasis during WD.”
Cannabinoid Receptor Type 2 Agonist Attenuates Acute Neurogenic Pulmonary Edema by Preventing Neutrophil Migration after Subarachnoid Hemorrhage in Rats.
“We evaluated whether JWH133, a selective cannabinoid type 2 receptor (CB2R) agonist, prevented neurogenic pulmonary edema (NPE) after subarachnoid hemorrhage (SAH) by attenuating inflammation…
CB2R agonist ameliorated lung permeability by inhibiting leukocyte trafficking and protecting tight junction proteins in the lung of NPE after SAH.”
GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis.
“Tumor cell migration and adhesion constitute essential features of metastasis. G protein-coupled receptor 55 (GPR55), a lysophospholipid receptor, has been shown to play an important role in carcinogenesis. Here, we investigated the involvement of GPR55 in migration and metastasis of colon cancer cells.
GPR55 antagonist CID16020046, cannabidiol, a putative GPR55 antagonist, and GPR55 siRNA were used to block GPR55 activity in HCT116 colon cancer cells.
In a mouse model of metastasis, the arrest of HCT116 cancer cells in the liver was reduced after treatment with CID16020046 or cannabidiol.
CONCLUSIONS AND IMPLICATIONS:
GPR55 is involved in the migratory behavior of colon carcinoma cells and may serve as a pharmacological target for the prevention of metastasis.”
http://www.ncbi.nlm.nih.gov/pubmed/26436760
“Pharmacological Characterization of GPR55, A Putative Cannabinoid Receptor” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874616/
Endocannabinoids and the Cardiovascular System in Health and Disease.
“The endocannabinoid system is widely distributed throughout the cardiovascular system.
Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders.
In shock, endocannabinoids released within blood mediate the associated hypotension through CB1 activation. In hypertension, there is evidence for changes in the expression of CB1, and CB1 antagonism reduces blood pressure in obese hypertensive and diabetic patients.
The endocannabinoid system is also upregulated in cardiac pathologies.
This is likely to be cardioprotective, via CB2 and CB1 (lesser extent).
In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids.
Endocannabinoids have positive (CB2) and negative effects (CB1) on the progression of atherosclerosis. However, any negative effects of CB1 may not be consequential, as chronic CB1 antagonism in large scale human trials was not associated with significant reductions in atheroma.
In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB1, CB2, TRPV1 and PPARα.
Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.”
Endocannabinoids and Their Pharmacological Actions.
“The endocannabinoid system consists of G protein-coupled cannabinoid CB1 and CB2 receptors, of endogenous compounds known as endocannabinoids that can target these receptors, of enzymes that catalyse endocannabinoid biosynthesis and metabolism, and of processes responsible for the cellular uptake of some endocannabinoids.
This review presents in vitro evidence that most or all of the following 13 compounds are probably orthosteric endocannabinoids since they have all been detected in mammalian tissues in one or more investigation, and all been found to bind to cannabinoid receptors, probably to an orthosteric site: anandamide, 2-arachidonoylglycerol, noladin ether, dihomo-γ-linolenoylethanolamide, virodhamine, oleamide, docosahexaenoylethanolamide, eicosapentaenoylethanolamide, sphingosine, docosatetraenoylethanolamide, N-arachidonoyldopamine, N-oleoyldopamine and haemopressin.
In addition, this review describes in vitro findings that suggest that the first eight of these compounds can activate CB1 and sometimes also CB2 receptors and that another two of these compounds are CB1 receptor antagonists (sphingosine) or antagonists/inverse agonists (haemopressin).
Evidence for the existence of at least three allosteric endocannabinoids is also presented. These endogenous compounds appear to target allosteric sites on cannabinoid receptors in vitro, either as negative allosteric modulators of the CB1 receptor (pepcan-12 and pregnenolone) or as positive allosteric modulators of this receptor (lipoxin A4) or of the CB2 receptor (pepcan-12).
Also discussed are current in vitro data that indicate the extent to which some established or putative orthosteric endocannabinoids seem to target non-cannabinoid receptors and ion channels, particularly at concentrations at which they have been found to interact with CB1 or CB2 receptors.”