Category Archives: Endocannabinoid System

2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons.

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“The contribution of two major endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), in the regulation of fear expression is still unknown. We analyzed the role of different players of the endocannabinoid system on the expression of a strong auditory-cued fear memory in male mice by pharmacological means…

Our findings suggest that increased AEA levels mediate acute fear relief, whereas increased 2-AG levels promote the expression of conditioned fear primarily via CB1 on GABAergic neurons.”

http://www.ncbi.nlm.nih.gov/pubmed/25814137

http://www.thctotalhealthcare.com/category/post-traumatic-stress-disorder-ptsd/

Cannabinoids to treat spinal cord injury.

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“Spinal Cord Injury (SCI) is a devastating condition for which there is no standard treatment beyond rehabilitation strategies. In this review, we discuss the current knowledge on the use of cannabinoids to treat this condition.

The endocannabinoid system is expressed in the intact spinal cord, and it is dramatically upregulated after lesion. Endogenous activation of this system counteracts secondary damage following SCI, and treatments with endocannabinoids or synthetic cannabinoid receptor agonists promote a better functional outcome in experimental models.

The use of cannabinoids in SCI is a new research field and many questions remain open. Here, we discuss caveats and suggest some future directions that may help to understand the role of cannabinoids in SCI and how to take advantage of this system to regain functions after spinal cord damage.”

http://www.ncbi.nlm.nih.gov/pubmed/25805333

http://www.thctotalhealthcare.com/category/spinal-cord-injury/

Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum.

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“In the largest data set of healthy participants so far, we provide evidence for a modest increase in human striatal dopamine transmission after administration of THC compared to other drugs of abuse.

This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.”

http://www.ncbi.nlm.nih.gov/pubmed/25801289

http://www.thctotalhealthcare.com/category/schizophrenia/

The Medicinal Chemistry of Cannabinoids.

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“The endocannabinoid system (ECS) comprises the two well characterized Gi/o -protein coupled receptors (CB1, CB2), their endogenous lipid ligands and the enzymes involved in their biosynthesis and biotransformation.

Drug discovery efforts relating to the ECS have been focused mainly on the two cannabinoid receptors and the two endocannabinoid deactivating enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL).

This review provides an overview of cannabinergic agents used in drug research and those being explored clinically.”

 http://www.ncbi.nlm.nih.gov/pubmed/25801236

Inhibition of monoacylglycerol lipase mediates a cannabinoid 1-receptor dependent delay of kindling progression in mice.

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“Endocannabinoids, including 2-arachidonoylglycerol (2-AG), activate presynaptic cannabinoid type 1 receptors (CB1R) on inhibitory and excitatory neurons, resulting in a decreased release of neurotransmitters.

Event-specific activation of the endocannabinoid system by inhibition of the endocannabinoid degrading enzymes may offer a promising strategy to selectively activate CB1Rs at the site of excessive neuronal activation with the overall goal to prevent the development epilepsy.

The aim of this study was to investigate the impact of monoacylglycerol lipase (MAGL) inhibition on the development and progression of epileptic seizures in the kindling model of temporal lobe epilepsy.

In conclusion, the data demonstrate that indirect CB1R agonism delays the development of generalized epileptic seizures, but has no relevant acute anticonvulsive effects.

Furthermore, we confirmed that the effects of JZL184 on kindling progression are CB1R mediated.

Thus, the data indicate that the endocannabinoid 2-AG might be a promising target for an anti-epileptogenic approach.”

Endocannabinoid signaling at the periphery: 50 years after THC.

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“In 1964, the psychoactive ingredient of Cannabis sativa, Δ9-tetrahydrocannabinol (THC), was isolated. Nearly 30 years later the endogenous counterparts of THC, collectively termed endocannabinoids (eCBs), were discovered: N-arachidonoylethanolamine (anandamide) (AEA) in 1992 and 2-arachidonoylglycerol (2-AG) in 1995.

Since then, considerable research has shed light on the impact of eCBs on human health and disease, identifying an ensemble of proteins that bind, synthesize, and degrade them and that together form the eCB system (ECS). eCBs control basic biological processes including cell choice between survival and death and progenitor/stem cell proliferation and differentiation.

Unsurprisingly, in the past two decades eCBs have been recognized as key mediators of several aspects of human pathophysiology and thus have emerged to be among the most widespread and versatile signaling molecules ever discovered.

Here some of the pioneers of this research field review the state of the art of critical eCB functions in peripheral organs. Our community effort is aimed at establishing consensus views on the relevance of the peripheral ECS for human health and disease pathogenesis, as well as highlighting emerging challenges and therapeutic hopes.”

http://www.ncbi.nlm.nih.gov/pubmed/25796370

For whom the endocannabinoid tolls: Modulation of innate immune function and implications for psychiatric disorders.

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“Over the past decade, there has been increasing evidence demonstrating that the endocannabinoid system can elicit potent modulatory effects on inflammatory processes, with clinical and preclinical evidence demonstrating beneficial effects on disease severity and symptoms in several inflammatory conditions.

This review examines the evidence supporting a modulatory effect of endocannabinoids on TLR-mediated immune responses both peripherally and centrally, and the implications for psychiatric disorders such as depression and schizophrenia.

CLASSES OF CANNABINOID-BASED PHARMACOLOGICAL AGENTS CITED IN THE REVIEW: Nonselective CB1/CB2 agonists: Δ9-THC, HU210, CP55940, WIN55,212-2 Selective CB2 agonists: JWH-015 FAAH inhibitors: URB597, AA-5HT MAGL/ABHD6 inhibitors: JZL184, MJN110, KML129, WWL70 Endocannabinoid reuptake inhibitors: UCM707, OMDM1/2, AM404.”

http://www.ncbi.nlm.nih.gov/pubmed/25794989

The endocannabinoid system and its therapeutic implications in rheumatoid arthritis.

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“Since the discovery of the endogenous receptor for Δ9-tetrahydrocannabinol, a main constituent of marijuana, the endocannabinoid system (comprising cannabinoid receptors and their endogenous ligands, as well as the enzymes involved in their metabolic processes) has been implicated as having multiple regulatory functions in many central and peripheral conditions, including rheumatoid arthritis (RA).

RA is an immune-mediated inflammatory disease that is associated with the involvement of many kinds of cells (such as fibroblastlike synoviocytes [FLSs], osteoclasts, T cells, B cells, and macrophages) and molecules (such as interleukin-1β, tumor necrosis factor-α, interleukin-6, matrix metalloproteinases [MMPs], and chemokines). Increasing evidence suggests that the endocannabinoid system, especially cannabinoid receptor 2 (CB2), has an important role in the pathophysiology of RA.

Many members of the endocannabinoid system are reported to inhibit synovial inflammation, hyperplasia, and cartilage destruction in RA.

In particular, specific activation of CB2 may relieve RA by inhibiting not only the production of autoantibodies, proinflammatory cytokines, and MMPs, but also bone erosion, immune response mediated by T cells, and the proliferation of FLSs.

In this review, we will discuss the possible functions of the endocannabinoid system in the modulation of RA, which may be a potential target for treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/25791728

http://www.thctotalhealthcare.com/category/rheumatoid-arthritis-2/

 

The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs-A practical view.

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“The endocannabinoid system, comprising cannabinoid CB1 and CB2 receptors, their endogenous ligands anandamide and 2-arachidonoylglyerol, and their synthetic and metabolic enzymes, are involved in many biological processes in the body, ranging from appetite to bone turnover.

Compounds inhibiting the breakdown of anandamide and 2-arachidonoylglycerol increase brain levels of these lipids and thus modulate endocannabinoid signalling.

In the present review, the preclinical evidence that these enzymes are good targets for development of novel therapies for anxiety and depression are discussed from a practical, rather than mechanistic, point of view.

It is concluded that the preclinical data are promising, albeit tempered by problems of tolerance as well as effects upon learning and memory for irreversible monoacylglycerol lipase inhibitors, and limited by a focus upon male rodents alone.

Clinical data so far has been restricted to safety studies with inhibitors of anandamide hydrolysis and a hitherto unpublished study on such a compound in elderly patients with major depressive disorders, but under the dose regimes used, they are well tolerated and show no signs of “cannabis-like” behaviours.”

http://www.ncbi.nlm.nih.gov/pubmed/25791296

In Vivo imaging of the cannabinoid CB1 receptor with positron emission tomography.

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“Positron emission tomography (PET) can visualize and quantify receptors and other targets in the living human brain, and recent progress in radioligand development has enabled measurement of cannabinoid CB1 receptors. Cannabinoid CB1 receptors have been implicated in multiple human diseases, such as obesity, mood disorders, and addiction. First in vivo human studies have shown distinctive spatial and temporal alterations in cannabinoid CB1 receptor binding in addictive disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/25788235