Category Archives: Endocannabinoid System

Endocannabinoid modulation of inflammatory hyperalgesia in the IFN-α mouse model of depression.

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Brain, Behavior, and Immunity“Depression is a well-recognised effect of long-term treatment with interferon-alpha (IFN-α), a widely used treatment for chronic viral hepatitis and malignancy. In addition to the emotional disturbances, high incidences of painful symptoms such as headache and joint pain have also been reported following IFN-α treatment.

The endocannabinoid system plays an important role in emotional and nociceptive processing, however it is unknown whether repeated IFN-α administration induces alterations in this system.

The present study investigated nociceptive responding in the IFN-α-induced mouse model of depression and associated changes in the endocannabinoid system. Furthermore, the effects of modulating peripheral endocannabinoid tone on inflammatory pain-related behaviour in the IFN-α model was examined.

In summary, increasing peripheral endocannabinoid tone attenuates inflammatory hyperalgesia induced following repeated IFN-α administration. These data provide support for the endocannabinoid system in mediating and modulating heightened pain responding associated with IFNα-induced depression.”

https://www.ncbi.nlm.nih.gov/pubmed/31505257

“Inflammatory hyperalgesia is associated with altered endocannabinoid levels. Enhancing peripheral endocannabinoid tone attenuates IFN-α related hyperalgesia.”

https://www.sciencedirect.com/science/article/pii/S0889159119306063?via%3Dihub

The “entourage effect”: Terpenes coupled with cannabinoids for the treatment of mood disorders and anxiety disorders.

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“Mood disorders are the most prevalent mental conditions encountered in psychiatric practice. Numerous patients suffering from mood disorders present with treatment-resistant forms of depression, co-morbid anxiety, other psychiatric disorders and bipolar disorders.

Standardized essential oils (such as that of Lavender officinalis) have been shown to exert clinical efficacy in treating anxiety disorders. As endocannabinoids are suggested to play an important role in major depression, generalized anxiety and bipolar disorders, Cannabis sativa, was suggested for their treatment.

The endocannabinoid system is widely distributed throughout the body including the brain, modulating many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids.

CB1 and CB2 receptors primarily serve as the binding sites for endocannabinoids as well as for phytocannabinoids, produced by cannabis inflorescences. However, ‘cannabis’ is not a single compound product but is known for its complicated molecular profile, producing a plethora of phytocannabinoids alongside a vast array of terpenes.

Thus, the “entourage effect” is the suggested positive contribution derived from the addition of terpenes to cannabinoids. Here we review the literature on the effects of cannabinoids and discuss the possibility of enhancing cannabinoid activity on psychiatric symptoms by the addition of terpenes and terpenoids.

Possible underlying mechanisms for the anti-depressant and anxiolytic effects are reviewed. These natural products may be an important potential source for new medications for the treatment of mood and anxiety disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31481004

http://www.eurekaselect.com/174648/article

Insights into biased signaling at cannabinoid receptors: synthetic cannabinoid receptor agonists.

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Biochemical Pharmacology“Cannabinoid receptors type 1 (CB1) and type 2 (CB2) are promising targets for a number of diseases, including obesity, neuropathic pain, and multiple sclerosis, among others.

Upon ligand-mediated activation of these receptors, multiple receptor conformations could be stabilized, resulting in a complex pattern of possible intracellular effects. Although numerous compounds have been developed and widely used to target cannabinoid receptors, their mode of action and signaling properties are often only poorly characterized.

From a drug development point of view, unraveling the underlying complex signaling mechanism could offer the possibility to generate medicines with the desired therapeutic profile.

Recently, an increased interest has emerged for the development of agonists that are signaling pathway-selective and thereby do not evoke on-target adverse effects. This phenomenon, in which specific pathways are preferred upon receptor activation by certain ligands, is also known as ‘biased signaling’.

For a particular group of cannabinoid receptor ligands (i.e. CB1/CB2 agonists), namely the synthetic cannabinoid receptor agonists (SCRAs), the research on biased signaling is still in its infancy and interesting outcomes are only recently being revealed.

Therefore, this review aims at providing insights into the recent knowledge about biased agonism mediated by SCRAs so far. In addition, as these outcomes are obtained using a distinct panel of functional assays, the accompanying difficulties and challenges when comparing functional outcomes are critically discussed. Finally, some guidance on the conceptualization of ideal in vitro assays for the detection of SCRA-mediated biased agonism, which is also relevant for compounds belonging to other chemical classes, is provided.”

https://www.ncbi.nlm.nih.gov/pubmed/31472128

https://www.sciencedirect.com/science/article/abs/pii/S0006295219303132?via%3Dihub

The cannabinoid receptor 1 is involved in renal fibrosis during chronic allograft dysfunction: Proof of concept.

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Publication cover image“Chronic allograft dysfunction (CAD), defined as the replacement of functional renal tissue by extracellular matrix proteins, remains the first cause of graft loss.

The aim of our study was to explore the potential role of the cannabinoid receptor 1 (CB1) during CAD.

Overall, our study strongly suggests an involvement of the cannabinoid system in the progression of fibrosis during CAD and indicates the therapeutic potential of CB1 antagonists in this pathology.”

https://www.ncbi.nlm.nih.gov/pubmed/31469511

https://onlinelibrary.wiley.com/doi/full/10.1111/jcmm.14570

Interplay of liver-heart inflammatory axis and cannabinoid 2 receptor signalling in an experimental model of hepatic cardiomyopathy.

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Publication cover image“Hepatic cardiomyopathy, a special type of heart failure develops in up to 50% of patients with cirrhosis and is a major determinant of survival. However, there is no reliable model of hepatic cardiomyopathy in mice. Herein we aimed to characterize the detailed hemodynamics of mice with bile-duct ligation (BDL)-induced liver fibrosis, by monitoring echocardiography and intracardiac pressure-volume (PV) relationships and myocardial structural alterations. Treatment of mice with a selective cannabinoid-2 receptor (CB2 -R) agonist, known to attenuate inflammation and fibrosis, was used to explore the impact of liver inflammation, fibrosis on cardiac function.

MAIN RESULTS:

BDL induced massive inflammation (increased leukocyte infiltration, inflammatory cytokines and chemokines), oxidative stress, microvascular dysfunction, and fibrosis in the liver. These pathological changes were accompanied by impaired diastolic, systolic and macrovascular functions, cardiac inflammation (increased MIP1, interleukin-1, P-selectin, CD45+ cells) and oxidative stress (increased malondialdehyde, 3-nitrotyrosine and NADPH-oxidases). CB2 -R up-regulation was observed both in livers and hearts of mice exposed to BDL. CB2 -R activation markedly improved hepatic inflammation, impaired microcirculation, fibrosis. CB2 -R activation also decreased serum TNF-alpha levels, and improved cardiac dysfunction, myocardial inflammation and oxidative stress underlining the importance of inflammatory mediators in the pathology of hepatic cardiomyopathy.

CONCLUSION:

We propose BDL-induced cardiomyopathy in mice as a model for hepatic/cirrhotic cardiomyopathy. This cardiomyopathy, similarly to cirrhotic cardiomyopathy in humans, is characterized by systemic hypotension, impaired macro- and microvascular function accompanied by both systolic and diastolic dysfunction. Our results indicate that the liver-heart inflammatory axis has a pivotal pathophysiological role in the development of hepatic cardiomyopathy. Thus, controlling liver and/or myocardial inflammation (e.g. with selective CB2-R agonists) may delay/prevent the development of cardiomyopathy in severe liver disease. ”

https://www.ncbi.nlm.nih.gov/pubmed/31469200

https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.30916

Δ8 -Tetrahydrocannabivarin has potent anti-nicotine effects in multiple rodent models of nicotine dependence.

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British Journal of Pharmacology banner“Both types of cannabinoid receptors – CB1 and CB2 – regulate brain functions relating to addictive drug-induced reward and relapse. CB1 receptor antagonists and CB2 receptor agonists have anti-addiction efficacy, in animal models, against a broad range of addictive drugs.

Δ9 -Tetrahydrocannabivarin (Δ9 -THCV) – a cannabis constituent – acts as a CB1 antagonist and a CB2 agonist. Δ8 -Tetrahydrocannabivarin (Δ8 -THCV) is a Δ9 -THCV analogue with similar combined CB1 antagonist/CB2agonist properties.

KEY RESULTS:

Δ8 -THCV significantly attenuated intravenous nicotine self-administration, and both cue-induced and nicotine-induced relapse to nicotine-seeking behavior in rats. Δ8 -THCV also significantly attenuated nicotine-induced conditioned place preference and nicotine withdrawal in mice.

CONCLUSIONS AND IMPLICATIONS:

We conclude that Δ8 -THCV may have therapeutic potential for the treatment of nicotine dependence. We also suggest that tetrahydrocannabivarins should be tested for possible anti-addiction efficacy in a broader range of preclinical animal models, against other addictive drugs, and eventually in humans.”

https://www.ncbi.nlm.nih.gov/pubmed/31454413

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14844

Activation of Cannabinoid Receptors Promote Periodontal Cell Adhesion and Migration.

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Journal of Clinical Periodontology banner“Medical and recreational cannabis use is increasing significantly, but its impacts on oral health remains unclear.

The aim of this study is to investigate the effects of tetrahydrocannabinol (THC), the major active component in cannabis, on periodontal fibroblast cell adhesion and migration to explore its role in periodontal regeneration and wound healing.

RESULTS:

Both CB1 and CB2 were expressed in periodontal tissues but with different expression patterns. THC promoted periodontal cell wound healing by inducing HPLF cell adhesion and migration. This was mediated by focal adhesion kinase (FAK) activation and its modulation of MAPK activities. The effect of cannabinoids on periodontal fibroblast cell adhesion and migration were mainly dependent on the CB2.

CONCLUSION:

These results suggested that cannabinoids may contribute to developing new therapeutics for periodontal regeneration and wound healing.”

https://www.ncbi.nlm.nih.gov/pubmed/31461164

https://onlinelibrary.wiley.com/doi/abs/10.1111/jcpe.13190

Therapeutic potential of cannabinoid receptor 2 in the treatment of diabetes mellitus and its complications.

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European Journal of Pharmacology“The biological effects of endocannabinoid system are mediated by two types of receptors, cannabinoid 1 (CB1) and cannabinoid 2 receptor (CB2). They play a pivotal role in the management of pain, inflammation, cancer, obesity and diabetes mellitus.

CB2 receptor activity downregulation is hallmark of inflammation and oxidative stress. Strong evidence display the relation between activation of CB2 receptors with decrease in the pro-inflammatory cytokines and pro-apoptotic factors. Numerous in vitro and in vivo studies have been validated to confirm the role of CB2 receptor in the management of obesity, hyperlipidemia and diabetes mellitus by regulating glucose and lipid metabolism.

Activation of CB2 receptor has led to reduction of inflammatory cytokines; tumor necrosis factor-alpha (TNF-α), Interleukin 6 (IL-6), Nuclear factor kappa beta (NF-κβ) and also amelioration of reactive oxygen species and reactive nitrogen species playing role in apoptosis. Many studies confirmed the role of CB2 receptors in the insulin secretion via facilitating calcium entry into the pancreatic β-cells. CB2 receptors also displayed improvement in the neuronal and renal functions by decreasing the oxidative stress and downregulating inflammatory cascade.

The present review addresses, potential role of CB2 receptor activation in management of diabetes and its complications. It also includes the role of CB2 receptors as an anti-oxidant, anti-apoptotic and anti-inflammatory for the treatment of DM and its complications. Also, an informative summary of CB2 receptor agonist drugs is provided with their potential role in the reduction of glucose levels, increment in the insulin levels, decrease in the hyperglycaemic oxidative stress and inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31461639

https://www.sciencedirect.com/science/article/pii/S0014299919305801?via%3Dihub

Cannabinoids and Mental Health, Part 1: The Endocannabinoid System and Exogenous Cannabinoids.

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Image result for j psychosoc nurs ment health serv“The increasing public acceptance of cannabis and the proliferation of cannabis products in the marketplace has coincided with more patients using the drug as a substitute for psychiatric medications or as an adjunctive treatment modality for psychiatric conditions, despite limited evidence of efficacy. With a goal of furthering harm-reduction efforts in psychiatric nursing, the current article reviews the fundamentals of the endocannabinoid system in humans and the exogenous phytocannabinoids that act on this regulatory neurotransmitter system. The basics of cannabis botany are also reviewed to help nurse clinicians understand the heterogeneous nature of cannabis products. This foundational knowledge will help improve clinical interactions with patients who use cannabis and provide the necessary understanding of cannabinoids needed to undertake further scientific query into their purported benefits in psychiatric disease states.”

https://www.ncbi.nlm.nih.gov/pubmed/31461513

Impaired brain endocannabinoid tone in the activity-based model of anorexia nervosa.

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International Journal of Eating Disorders banner“Despite the growing knowledge on the functional relationship between an altered endocannabinoid (eCB) system and development of anorexia nervosa (AN), to date no studies have investigated the central eCB tone in the activity-based anorexia (ABA) model that reproduces key aspects of human AN.

These data demonstrate an altered brain eCB tone in ABA rats, further supporting the involvement of an impaired eCB system in AN pathophysiology that may contribute to the maintenance of some symptomatic aspects of the disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31456239

https://onlinelibrary.wiley.com/doi/abs/10.1002/eat.23157