Tag Archives: endocannabinoid system

Controlled downregulation of the cannabinoid CB1 receptor provides a promising approach for the treatment of obesity and obesity-derived type 2 diabetes.

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“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.”

http://www.ncbi.nlm.nih.gov/pubmed/26498013

Peripherally Restricted Cannabinoids for the Treatment of Pain.

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“The use of cannabinoids for the treatment of chronic diseases has increased in the United States, with 23 states having legalized the use of marijuana.

Although currently available cannabinoid compounds have shown effectiveness in relieving symptoms associated with numerous diseases, the use of cannabis or cannabinoids is still controversial mostly due to their psychotropic effects (e.g., euphoria, laughter) or central nervous system (CNS)-related undesired effects (e.g., tolerance, dependence).

A potential strategy to use cannabinoids for medical conditions without inducing psychotropic or CNS-related undesired effects is to avoid their actions in the CNS.

This approach could be beneficial for conditions with prominent peripheral pathophysiologic mechanisms (e.g., painful diabetic neuropathy, chemotherapy-induced neuropathy).

In this article, we discuss the scientific evidence to target the peripheral cannabinoid system as an alternative to cannabis use for medical purposes, and we review the available literature to determine the pros and cons of potential strategies that can be used to this end.”

http://www.ncbi.nlm.nih.gov/pubmed/26497478

The Cannabinoid Receptor CB1 Interacts with the WAVE1 Complex and Plays a Role in Actin Dynamics and Structural Plasticity in Neurons.

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“The molecular composition of the cannabinoid type 1 (CB1) receptor complex beyond the classical G-protein signaling components is not known.

Using proteomics on mouse cortex in vivo, we pulled down proteins interacting with CB1 in neurons and show that the CB1 receptor assembles with multiple members of the WAVE1 complex and the RhoGTPase Rac1 and modulates their activity…

This study reports novel signaling mechanisms for cannabinoidergic modulation of the nervous system and demonstrates a previously unreported role for the WAVE1 complex in therapeutic applications of cannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/26496209

Alcohol Versus Cannabinoids: A Review of Their Opposite Neuro-Immunomodulatory Effects and Future Therapeutic Potentials.

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“Due to the legalization of marijuana and the increased demand for cannabis and alcohol consumption, research efforts highlighting the biomedical consequences of the use of alcohol and cannabinoids are not only relevant to the substance abuse scientific field, but are also of public health interest.

Moreover, an overview of the recent literature about alcohol and cannabinoids neuro-immunomodulatory effects highlighting their future therapeutic potentials will provide a significant contribution to science and medicine.

Therefore, in the current review, we will first discuss briefly the prevalence of alcohol and marijuana abuse, followed by a discussion on the individual effects of alcohol and cannabinoids on the immune system; then, we will focus on the role of endocannabinoids on the alcohol-induced inflammatory effects.

In addition, the review also incorporates cytokine array data obtained from human monocyte-derived dendritic cells, providing a different perspective on the alcohol and cannabinoid abuse divergent effects on cytokine production.

The final section will highlight the therapeutic potential of cannabinoid receptors and the novel strategies to treat alcohol dependence as determined by in vitro, in vivo and clinical studies.”

http://www.ncbi.nlm.nih.gov/pubmed/26478902

Further Characterization of Hemopressin Peptide Fragments in the Opioid and Cannabinoid Systems.

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“Hemopressin, so-called because of its hypotensive effect, belongs to the derivatives of the hemoglobin α-chain. It was isolated from rat brain membrane homogenate by the use of catalytically inactive forms of endopeptidase 24.15 and neurolysin. Hemopressin has antihyperalgesic features that cannot be prevented by the opioid receptor antagonist, naloxone.

Here, we further confirm that hemopressins can modulate CB1 receptors and can have a slight modulatory effect on the opioid system.”

http://www.ncbi.nlm.nih.gov/pubmed/26465932

Type 1 cannabinoid receptor modulates water deprivation-induced homeostatic responses.

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“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.”

http://www.ncbi.nlm.nih.gov/pubmed/26468265

Training-Associated Emotional Arousal Shapes Endocannabinoid Modulation of Spatial Memory Retrieval in Rats.

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“Variations in environmental aversiveness influence emotional memory processes in rats. We have previously shown that cannabinoid effects on memory are dependent on the stress level at the time of training as well as on the aversiveness of the environmental context. Here, we investigated whether the hippocampal endocannabinoid system modulates memory retrieval depending on the training-associated arousal level…

The present findings indicate that the endocannabinoid 2-AG in the hippocampus plays a key role in the selective regulation of spatial memory retrieval of stressful experience, shedding light on the neurobiological mechanisms involved in the impact of stress effects on memory processing.

SIGNIFICANCE STATEMENT:

Endogenous cannabinoids play a central role in the modulation of memory for emotional events. Here we demonstrate that the endocannabinoid 2-arachidonoylglycerol in the hippocampus, a brain region crucially involved in the regulation of memory processes, selectively modulates spatial memory recall of stressful experiences. Thus, our findings provide evidence that the endocannabinoid 2-arachidonoylglycerol is a key player in mediating the impact of stress on memory retrieval.

These findings can pave the way to new potential therapeutic intervention for the treatment of neuropsychiatric disorders, such as post-traumatic stress disorder, where a previous exposure to traumatic events could alter the response to traumatic memory recall leading to mental illness.”

http://www.ncbi.nlm.nih.gov/pubmed/26468197

Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors.

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“Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors.

Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo.

We investigated whether human lung-resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors…

Activation of cannabinoid receptors on tissue-resident macrophages might be a novel strategy to modulate macrophage-assisted vascular remodeling in cancer and chronic inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/26467187

Evaluation of cannabinoid CB1 and CB2 receptors expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients’ survival.

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Tumor Biology

“Cannabinoid receptors (CB1R and CB2R) constitute essential members of the endocannabinoid system (ECS) which participates in many different functions indispensable to homeostatic regulation in several tissues, exerting also antitumorigenic effects. The present study aimed to assess the clinical significance of CB1R and CB2R protein expression in mobile tongue squamous cell carcinoma (SCC). The present study provides evidence that CB1R and CB2R may play a role in the pathophysiological aspects of the mobile tongue SCC and even each molecule may constitute a potential target for the development of novel anti-cancer drugs for this type of malignancy.” http://www.ncbi.nlm.nih.gov/pubmed/26459312

https://link.springer.com/article/10.1007%2Fs13277-015-4182-8

The skeletal endocannabinoid system: clinical and experimental insights.

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“Recently, there has been a rapidly growing interest in the role of cannabinoids in the regulation of skeletal remodeling and bone mass, addressed in basic, translational and clinical research.

Since the first publications in 2005, there are more than 1000 publications addressing the skeletal endocannabinoid system.

This review focuses on the roles of the endocannabinoid system in skeletal biology via the cannabinoid receptors CB1, CB2 and others.

Endocannabinoids play important roles in bone formation, bone resorption and skeletal growth, and are sometimes age, gender, species and strain dependent. Controversies in the literature and potential therapeutic approaches targeting the endocannabinoid system in skeletal disorders are also discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/26457774