Category Archives: Endocannabinoid System

Emerging Class of Omega-3 Fatty Acid Endocannabinoids & Their Derivatives.

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Prostaglandins & Other Lipid Mediators

“Cannabinoid receptor activation is involved in homeostatic regulation of the body. These receptors are activated by cannabinoids, that include the active constituents of Cannabis sativa as well as endocannabinoids (eCBs). The eCBs are endogenously synthesized from the omega-6 and omega-3 polyunsaturated fatty acids (PUFAs). In summary, we outline the novel findings regarding a growing class of signaling molecules, omega-3 eCBs, that can control the physiological and pathophysiological processes in the body.” https://www.ncbi.nlm.nih.gov/pubmed/31085370

“Anti-inflammatory ω-3 endocannabinoid epoxides.”  https://www.ncbi.nlm.nih.gov/pubmed/28687674

“Antitumorigenic Properties of Omega-3 Endocannabinoid Epoxides.” https://www.ncbi.nlm.nih.gov/pubmed/29856219

Cannabinoid interactions with ion channels and receptors.

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“Cannabidiol (CBD), the non-psychoactive component of Cannabis sativa, acts on a diverse selection of membrane proteins with promising therapeutic potential in epilepsy and chronic pain. In this review, we will outline the studies that report reproducible results of CBD and other cannabinoids changing membrane channel function, with particular interest on Nav. Nav are implicated in fatal forms of epilepsy and are also associated with chronic pain. This makes Nav potential targets for CBD interaction since it has been reported to reduce pain and seizures. This discovery will not only prompt further research towards CBD’s characterization, but also promotes the application of cannabinoids as potentially therapeutic compounds for diseases like epilepsy and pain.” https://www.ncbi.nlm.nih.gov/pubmed/31088312
https://www.tandfonline.com/doi/full/10.1080/19336950.2019.1615824

Towards A Molecular Understanding of The Cannabinoid Related Orphan Receptor GPR18: A Focus on Its Constitutive Activity.

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“The orphan G-protein coupled receptor (GPCR), GPR18, has been recently proposed as a potential member of the cannabinoid family as it recognizes several endogenous, phytogenic, and synthetic cannabinoids. Potential therapeutic applications for GPR18 include intraocular pressure, metabolic disorders, and cancer. GPR18 has been reported to have high constitutive activity, i.e., activation/signaling occurs in the absence of an agonist. This activity can be reduced significantly by the A3.39N mutation. At the intracellular (IC) ends of (transmembrane helices) TMH3 and TMH6 in GPCRs, typically, a pair of oppositely charged amino acids form a salt bridge called the “ionic lock”. Breaking of this salt bridge creates an IC opening for coupling with G protein. The GPR18 “ionic lock” residues (R3.50/S6.33) can form only a hydrogen bond. In this paper, we test the hypothesis that the high constitutive activity of GPR18 is due to the weakness of its “ionic lock” and that the A3.39N mutation strengthens this lock. To this end, we report molecular dynamics simulations of wild-type (WT) GPR18 and the A3.39N mutant in fully hydrated (POPC) phophatidylcholine lipid bilayers. Results suggest that in the A3.39N mutant, TMH6 rotates and brings R3.50 and S6.33 closer together, thus strengthening the GPR18 “ionic lock”.”

https://www.ncbi.nlm.nih.gov/pubmed/31075933

https://www.mdpi.com/1422-0067/20/9/2300

Endocannabinoid System in Spinocerebellar Ataxia Type-3 and Other Autosomal-Dominant Cerebellar Ataxias: Potential Role in Pathogenesis and Expected Relevance as Neuroprotective Targets.

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“Spinocerebellar ataxias (SCAs) are a group of hereditary and progressive neurological disorders characterized by a loss of balance and motor coordination. SCAs have no cure and effective symptom-alleviating and disease-modifying therapies are not currently available. However, based on results obtained in studies conducted in murine models and information derived from analyses in post-mortem tissue samples from patients, which show notably higher levels of CB1 receptors found in different cerebellar neuronal subpopulations, the blockade of these receptors has been proposed for acutely modulating motor incoordination in cerebellar ataxias, whereas their chronic activation has been proposed for preserving specific neuronal losses. Additional studies in post-mortem tissues from SCA patients have also demonstrated elevated levels of CB2 receptors in Purkinje neurons as well as in glial elements in the granular layer and in the cerebellar white matter, with a similar profile found for endocannabinoid hydrolyzing enzymes, then suggesting that activating CB2 receptors and/or inhibiting these enzymes may also serve to develop cannabinoid-based neuroprotective therapies.”
https://www.ncbi.nlm.nih.gov/pubmed/31068788
“Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3.” https://www.ncbi.nlm.nih.gov/pubmed/27717809

Endocannabinoid contributions to alcohol habits and motivation: Relevance to treatment.

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Addiction Biology banner“Individuals with alcohol use disorder exhibit compulsive habitual behaviors that are thought to be, in part, a consequence of chronic and persistent use of alcohol.

The endocannabinoid system plays a critical role in habit learning and in ethanol self-administration, but the role of this neuromodulatory system in the expression of habitual alcohol seeking is unknown.

Here, we investigated the role of the endocannabinoid system in established alcohol habits using contingency degradation in male C57BL/6 mice.

These results demonstrate an important role for endocannabinoid signaling in the motivation to seek ethanol, in ethanol-motivated habits, and suggest that pharmacological manipulations of endocannabinoid signaling could be effective therapeutics for treating alcohol use disorder.”

https://www.ncbi.nlm.nih.gov/pubmed/31056846

https://onlinelibrary.wiley.com/doi/abs/10.1111/adb.12768

Using Cannabis to Treat Cancer-Related Pain.

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Seminars in Oncology Nursing

“OBJECTIVE: To describe which cannabinoids and terpenes are effective for treating pain.

CONCLUSION: Cannabis and cannabinoid medicines, as modulators of the endocannabinoid system, offer novel therapeutic options for the treatment of cancer-related pain, not only for patients who do not respond to conventional therapies, but also for patients who prefer to try cannabis as a first treatment option.

IMPLICATIONS FOR NURSING PRACTICE: Understanding the endocannabinoid system, cannabinoids, terpenes, routes of administration, potential drug interactions, clinical implications, and potential side effects ensures nurses can better assist patients who use cannabis for the treatment of cancer pain.”

https://www.ncbi.nlm.nih.gov/pubmed/31053395

https://www.sciencedirect.com/science/article/pii/S0749208119300609?via%3Dihub

Marijuana for Parkinson’s Disease?

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“Marijuana is popular in the United States and is being widely legalized for recreational and medicinal purposes. It remains a Schedule 1 substance without fully proven risks and benefits; yet, it is increasingly available in many US states and territories.

Cannabis might have medicinal efficacy in Parkinson’s disease as a form of medical marijuana. Endocannabinoid receptors exist throughout the nervous system and are documented to influence receptors affecting a wide variety of areas. Neuroprotective aspects might be induced by cannabis exposure that might yield benefit against the nigrostriatal degeneration of patients with Parkinson’s disease.

Animal investigations support suggestions of improvement in bradykinesia and/or tremors, but this is unsubstantiated in human studies. However, some patient surveys and anecdotal or case reports indicate that marijuana attenuates some motor manifestations of parkinsonism and also of non-motor, mood and/or cognitive symptoms. Medical marijuana might benefit motor and nonmotor aspects of Parkinson’s disease patients. Currently, these assertions are not substantiated in human investigations and cannabis can also induce side effects. Until studies clarify the safety and efficacy of pharmacotherapy with cannabis products, medical marijuana remains largely without scientific endorsement. Research has yet to document the full benefits, risks, and clinical applications of marijuana as a treatment for patients with Parkinson’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31037227

Emerging evidence for the antidepressant effect of cannabidiol and the underlying molecular mechanisms.

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Journal of Chemical Neuroanatomy

“Significant limitations with the currently available antidepressant treatment strategies have inspired research on finding new and more efficient drugs to treat depression. Cannabidiol (CBD) is a non-psychotomimetic component of Cannabis sativa, and emerges in this regard as a promising compound. In 2010, we were the first laboratory to demonstrate that CBD is effective in animal models of predictive of antidepressant effect, a finding now confirmed by several other groups. Recent evidence suggests that CBD promotes both a rapid and a sustained antidepressant effect in animal models. CBD has a complex pharmacology, with the ability to interact with multiple neurotransmitter systems involved in depression, including the serotonergic, glutamatergic, and endocannabinoid systems. Moreover, CBD induces cellular and molecular changes in brain regions related to depression neurobiology, such as increased Brain Derived Neurotrophic Factor (BDNF) levels and synaptogenesis in the medial prefrontal cortex, as well as it increases neurogenesis in the hippocampus. This review presents a comprehensive critical overview of the current literature related to the antidepressant effects of CBD, with focus at the possible mechanisms. Finally, challenges and perspectives for future research are discussed.”

https://www.ncbi.nlm.nih.gov/pubmed/31039391

https://www.sciencedirect.com/science/article/pii/S0891061818302114?via%3Dihub

Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications.

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ijms-logo “Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.”

https://www.ncbi.nlm.nih.gov/pubmed/31035653

https://www.mdpi.com/1422-0067/20/9/2109

Aging circadian rhythms and cannabinoids.

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Neurobiology of Aging

“Numerous aspects of mammalian physiology exhibit cyclic daily patterns known as circadian rhythms. However, studies in aged humans and animals indicate that these physiological rhythms are not consistent throughout the life span. The simultaneous development of disrupted circadian rhythms and age-related impairments suggests a shared mechanism, which may be amenable to therapeutic intervention.

Recently, the endocannabinoid system has emerged as a complex signaling network, which regulates numerous aspects of circadian physiology relevant to the neurobiology of aging.

Agonists of cannabinoid receptor-1 (CB1) have consistently been shown to decrease neuronal activity, core body temperature, locomotion, and cognitive function. Paradoxically, several lines of evidence now suggest that very low doses of cannabinoids are beneficial in advanced age.

One potential explanation for this phenomenon is that these drugs exhibit hormesis-a biphasic dose-response wherein low doses produce the opposite effects of higher doses. Therefore, it is important to determine the dose-, age-, and time-dependent effects of these substances on the regulation of circadian rhythms and other processes dysregulated in aging.

This review highlights 3 fields-biological aging, circadian rhythms, and endocannabinoid signaling-to critically assess the therapeutic potential of endocannabinoid modulation in aged individuals. If the hormetic properties of exogenous cannabinoids are confirmed, we conclude that precise administration of these compounds may bidirectionally entrain central and peripheral circadian clocks and benefit multiple aspects of aging physiology.”

https://www.ncbi.nlm.nih.gov/pubmed/31035036

https://www.sciencedirect.com/science/article/pii/S0197458019300867?via%3Dihub