Tag Archives: endocannabinoid system

The endocannabinoid anandamide causes endothelium-dependent vasorelaxation in human mesenteric arteries.

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“The endocannabinoid anandamide (AEA) causes vasorelaxation in animal studies.

Although circulating AEA levels are increased in many pathologies, little is known about its vascular effects in humans. The aim of this work was to characterise the effects of AEA in human arteries.

Post hoc analysis of the data set showed that overweight patients and those taking paracetamol had reduced vasorelaxant responses to AEA.

These data show that AEA causes moderate endothelium-dependent, NO-dependent vasorelaxation in human mesenteric arteries via activation of CB1 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27633407

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology.

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“Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS).

This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one Δ9-tetrahydrocannabinol, and 2) the adaptive pro-homeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs.

In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.”

http://www.ncbi.nlm.nih.gov/pubmed/27630175

Important role of endocannabinoid signaling in the development of functional vision and locomotion in zebrafish.

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“The developmental role of the endocannabinoid system still remains to be fully understood.

Here, we report the presence of a complete endocannabinoid system during zebrafish development and show that the genes that code for enzymes that catalyze the anabolism and catabolism (mgll and dagla) of the endocannabinoid, 2-AG (2-arachidonoylglycerol), as well as 2-AG main receptor in the brain, cannabinoid receptor type 1, are coexpressed in defined regions of axonal growth.

By using morpholino-induced transient knockdown of the zebrafish Daglα homolog and its pharmacologic rescue, we suggest that synthesis of 2-AG is implicated in the control of axon formation in the midbrain-hindbrain region and that animals that lack Daglα display abnormal physiological behaviors in tests that measure stereotyped movement and motion perception.

Our results suggest that the well-established role for 2-AG in axonal outgrowth has implications for the control of vision and movement in zebrafish and, thus, is likely common to all vertebrates.”

http://www.ncbi.nlm.nih.gov/pubmed/27623930

Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα.

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“Cannabinoids modulate intestinal permeability through CB1.

The endocannabinoid-like compounds oleoylethanolamine (OEA) and palmitoylethanolamine (PEA) play an important role in digestive regulation, and we hypothesized they would also modulate intestinal permeability.

OEA and PEA have endogenous roles and potential therapeutic applications in conditions of intestinal hyperpermeability and inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/27623929

Don’t Worry, Be Happy: Endocannabinoids and Cannabis at the Intersection of Stress and Reward.

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“Cannabis enables and enhances the subjective sense of well-being by stimulating the endocannabinoid system (ECS), which plays a key role in modulating the response to stress, reward, and their interactions.

The recent shift toward legalization of medical or recreational cannabis has renewed interest in investigating the physiological role of the ECS as well as the potential health effects, both adverse and beneficial, of cannabis.

Here we review our current understanding of the ECS and its complex physiological roles.

We discuss the implications of this understanding vis-á-vis the ECS’s modulation of stress and reward and its relevance to mental disorders in which these processes are disrupted (i.e., addiction, depression, posttraumatic stress disorder, schizophrenia), along with the therapeutic potential of strategies to manipulate the ECS for these conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/27618739

Spontaneous involution of pediatric low-grade gliomas: high expression of cannabinoid receptor 1 (CNR1) at the time of diagnosis may indicate involvement of the endocannabinoid system.

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“Pediatric low-grade gliomas (P-LGG) consist of a mixed group of brain tumors that correspond to the majority of CNS tumors in children.

Notably, they may exhibit spontaneous involution after subtotal surgical removal (STR). In this study, we investigated molecular indicators of spontaneous involution in P-LGG.

CONCLUSIONS:

The P-LGG, which remained stable or that presented spontaneous involution after STR, showed significantly higher CNR1 expression at the time of diagnosis.

We hypothesize that high expression levels of CNR1 provide tumor susceptibility to the antitumor effects of circulating endocannabinoids like anandamide, resulting in tumor involution.

This corroborates with reports suggesting that CNR1 agonists and activators of the endocannabinoid system may represent therapeutic opportunities for children with LGG.

We also suggest that CNR1 may be a prognostic marker for P-LGG.

This is the first time spontaneous involution of P-LGG has been suggested to be induced by endocannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/27613640

Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation.

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“Since the discovery of the endocannabinoid system consisting of cannabinoid receptors, endogenous ligands, and biosynthetic and metabolizing enzymes, interest has been renewed in investigating the promise of cannabinoids as therapeutic agents.

Abundant evidence indicates that cannabinoids modulate immune responses.

An inflammatory response is triggered when innate immune cells receive a danger signal provided by pathogen- or damage-associated molecular patterns engaging pattern-recognition receptors.

Toll-like receptor family members are prominent pattern-recognition receptors expressed on innate immune cells.

Cannabinoids suppress Toll-like receptor-mediated inflammatory responses.

Innate immune cells express cannabinoid receptors and produce endogenous cannabinoids.

Hence, innate immune cells may play a role in regulating endocannabinoid homeostasis, and, in turn, the endocannabinoid system modulates local inflammatory responses.

Studies designed to probe the interaction between the innate immune system and the endocannabinoid system may identify new potential molecular targets in developing therapeutic strategies for chronic inflammatory diseases.

This review discusses the endocannabinoid system and Toll-like receptor family and evaluates the interaction between them.”

http://www.ncbi.nlm.nih.gov/pubmed/27597805

2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factor-alpha production in murine macrophages, and in mice.

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“2-Arachidonylglycerol (2-AG) inhibits the production in vitro of tumor necrosis factor-alpha (TNF-alpha) by mouse macrophages, as well as in mice. It has no effect on the production of nitric oxide (NO). The effect on TNF-alpha is enhanced when 2-AG is administered together with 2-linoleylglycerol (2-Lino-G) and 2-palmitylglycerol (2-PalmG), an ‘entourage effect’ previously noted in several behavioral and binding assays. 2-AG also suppresses the formation of radical oxygen intermediates.”

 http://www.ncbi.nlm.nih.gov/pubmed/11011050

Characterization of peripheral cannabinoid receptor expression and clinical correlates in schizophrenia.

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“The relationship between cannabinoid receptor signaling and psychosis vulnerability requires further exploration.

The endocannabinoid signaling system is extensive, with receptors exerting regulatory functions in both immune and central nervous systems.

In the brain, cannabinoid receptors (CBR) directly modulate neurotransmitter systems.

In the peripheral lymphocyte, CBRs mediate cytokine release, with dysregulated cytokine levels demonstrated in schizophrenia.

These results continue to support dysregulation of particular aspects of the endocannabinoid signaling system in participants with schizophrenia selected for the self-reported absence of marijuana abuse/dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/27591408

Interaction between interleukin-1β and type-1 cannabinoid receptor is involved in anxiety-like behavior in experimental autoimmune encephalomyelitis.

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“Mood disorders, including anxiety and depression, are frequently diagnosed in multiple sclerosis (MS) patients, even independently of the disabling symptoms associated with the disease.

Anatomical, biochemical, and pharmacological evidence indicates that type-1 cannabinoid receptor (CB1R) is implicated in the control of emotional behavior and is modulated during inflammatory neurodegenerative diseases such as MS and experimental autoimmune encephalomyelitis (EAE).

We investigated whether CB1R could exert a role in anxiety-like behavior in mice with EAE. We performed behavioral, pharmacological, and electrophysiological experiments to explore the link between central inflammation, mood, and CB1R function in EAE.

Overall, results of the present investigation indicate that synaptic dysfunction linked to CB1R is involved in EAE-related anxiety and motivation-based behavior and contribute to clarify the complex neurobiological mechanisms underlying mood disorders associated to MS.

Collectively, our data contribute to clarify the synaptic and, at least in part, molecular basis of mood disturbances in EAE and, possibly, MS. Understanding the neurobiological underpinning of anxiety-like behavior in EAE mice is of crucial importance to optimize the treatment of mood disturbance in MS and, possibly, other neuroinflammatory diseases.

In this direction, targeting the endocannabinoid system may be a valid therapeutic tool for the treatment of both psychiatric and motor symptoms in MS patients.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009553/