Category Archives: Endocannabinoid System

[Cardiovascular effects of cannabinoids].

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“The psychoactive properties of cannabinoids, the biologically active constituents of the marijuana plant, have long been recognized. Recent research has revealed that cannabinoids elicit not only neurobehavioral, and immunological, but also profound cardiovascular effects.

Similar effects can be elicited by the endogenous ligand arachidonyl ethanolamine (anandamide) and 2-arachidonoyl-glycerol.

The biological effects of cannabinoids are mediated by specific receptors.

Two cannabinoid receptors have been identified so far: CB1-receptors are expressed by different cells of the brain and in peripheral tissues, while CB2-receptors were found almost exclusively in immune cells.

Through the use of a selective CB1 receptor antagonist and CB1 receptor-knockout mice the hypotensive and bradycardic effects of cannabinoids in rodents could be attributed to activation of peripheral CB1 receptors. In hemodynamic studies using the radioactive microsphere technique in anesthetized rats, cannabinoids were found to be potent CB1-receptor dependent vasodilators in the coronary and cerebrovascular beds.

Recent findings implicate the endogenous cannabinoid system in the pathomechanism of haemorrhagic, endotoxic and cardiogenic shock.

Finally, there is evidence that the extreme mesenteric vasodilation, portal hypertension and systemic hypotension present in advanced liver cirrhosis are also mediated by the endocannabinoid system.

These exciting, recent research developments indicate that the endogenous cannabinoid system plays an important role in cardiovascular regulation, and pharmacological manipulation of this system may offer novel therapeutic approaches in a variety of pathological conditions.”

Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling.

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“Cannabinoids include not only plant-derived compounds (of which delta9-tetrahydrocannabinol is the primary psychoactive ingredient of cannabis), but also synthetic agents and endogenous substances termed endocannabinoids which include anandamide (2-arachidonoylethanolamide) and 2-arachidonoylglycerol.

Cannabinoids act on specific, G-protein-coupled, receptors which are currently divided into two types, CB1 and CB2. Relatively selective agonists and antagonists for these receptors have been developed, although one agent (SR141716A) widely used as an antagonist at CB1 receptors has non-cannabinoid receptor-mediated effects at concentrations which are often used to define the presence of the CB1 receptor.

Both cannabinoid receptors are primarily coupled to Gi/o proteins and act to inhibit adenylyl cyclase. Stimulation of CB1 receptors also modulates the activity of K+ and Ca2+ channels and of protein kinase pathways including protein kinase B (Akt) which might mediate effects on apoptosis. CB, receptors may activate the extracellular signal-regulated kinase cascade through ceramide signalling.

Cannabinoid actions on the cardiovascular system have been widely interpreted as being mediated by CB1 receptors although there are a growing number of observations, particularly in isolated heart and blood vessel preparations, that suggest that other cannabinoid receptors may exist.

Interestingly, the currently identified cannabinoid receptors appear to be related to a wider family of lipid receptor, those for the lysophospholipids, which are also linked to Gi/o protein signalling.

Anandamide also activates vanilloid VR1 receptors on sensory nerves and releases the vasoactive peptide, calcitonin gene-related peptide (CGRP), which brings about vasodilatation through its action on CGRP receptors.

Current evidence suggests that endocannabinoids have important protective roles in pathophysiological conditions such as shock and myocardial infarction.

Therefore, their cardiovascular effects and the receptors mediating them are the subject of increasing investigative interest.”

http://www.ncbi.nlm.nih.gov/pubmed/15005177

[Cardiac and vascular effects of cannabinoids: toward a therapeutic use?].

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“Interest in cannabinoid pharmacology developed rapidly since the discovery of cannabinoids receptors and endocannabinoids. Modulation of this system is becoming a hot topic in cardiovascular pharmacology mainly at the light of recent findings.

Among them, cardiac effects of cannabinoids were described with respect to their probable participation to the well-studied preconditioning phenomenon.

Beneficial effects of post-infarction cannabinoids administration against ischemia-reperfusion injury were also reported.

Finally, pathological situations concerning the cardiovascular system and including brain ischemia, hemorrhagic and endotoxic shocks were reported to be linked with endocannabinoids.

However, the clinical use of cannabinoid receptors agonists or antagonists will depend on the development of non psychoactive compounds.”

http://www.ncbi.nlm.nih.gov/pubmed/15828464

The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy.

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“Ischemic heart disease is associated with inflammation, interstitial fibrosis and ventricular dysfunction prior to the development of heart failure.

Endocannabinoids and the cannabinoid receptor CB2 have been claimed to be involved, but their potential role in cardioprotection is not well understood. We therefore explored the role of the cannabinoid receptor CB2 during the initial phase of ischemic cardiomyopathy development prior to the onset of ventricular dysfunction or infarction.

… the endocannabinoid-CB2 receptor axis plays a key role in cardioprotection during the initial phase of ischemic cardiomyopathy development.”

http://www.ncbi.nlm.nih.gov/pubmed/24980781

The endocannabinoid anandamide during lactation increases body fat content and CB1 receptor levels in mice adipose tissue.

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“Type 1 cannabinoid receptors (CB1R) modulate energy balance; thus, their premature activation may result in altered physiology of tissues involved in such a function.

Activation of CB1R mainly occurs after binding to the endocannabinoid Anandamide (AEA).

The objective of this study was to evaluate the effects of AEA treatment during lactation on epididymal and body fat content, in addition to CB1R protein level at weaning.

This in vivo study shows for the first time that a progressive increase in body fat accumulation can be programmed in early stages of life by oral treatment with the endocannabinoid AEA, a fact associated with an increased amount of epididymal fat pads and a higher expression of CB1R in this tissue.”

http://www.ncbi.nlm.nih.gov/pubmed/26098446

CB2R orchestrates fibrogenesis through regulation of inflammatory response during the repair of skeletal muscle contusion.

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“Skeletal muscle injuries repair typically is an overlapping event between inflammation and tissue repair.

Our previous study has demonstrated that activation of cannabinoid receptor type 2 (CB2R) alleviates fibrosis in the repair of rat skeletal muscle contusion. Meanwhile, accumulated data show that CB2R stimulation exerts anti-inflammatory property in sepsis and cystitis…

In this study, we used selective agonist or antagonist of CB2R to observe the role of CB2R on inflammation and fibrogenesis during the repair of contused skeletal muscles in rats…

Our study demonstrated that CB2R orchestrates fibrogenesis through regulation of inflammatory response during the repair of skeletal muscle contusion.”

http://www.ncbi.nlm.nih.gov/pubmed/26097533

 

The influence of cannabinoids on learning and memory processes of the dorsal striatum.

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“Extensive evidence indicates that the mammalian endocannabinoid system plays an integral role in learning and memory…

A tentative conclusion based on the available data is that acute disruption of the endocannabinoid system with either agonists or antagonists impairs, whereas chronic cannabinoid exposure enhances, dorsal striatum-dependent S-R/habit memory.

CB1 receptors are required for multiple forms of striatal synaptic plasticity implicated in memory, including short-term and long-term depression.

Interactions with the hippocampus-dependent memory system may also have a role in some of the observed effects of cannabinoids on habit memory.

The impairing effect often observed with acute cannabinoid administration argues for cannabinoid-based treatments for human psychopathologies associated with a dysfunctional habit memory system (e.g. post-traumatic stress disorder and drug addiction/relapse).”

http://www.ncbi.nlm.nih.gov/pubmed/26092091

Anandamide, Acting via CB2 Receptors, Alleviates LPS-Induced Neuroinflammation in Rat Primary Microglial Cultures.

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“Microglial activation is a polarized process divided into potentially neuroprotective phenotype M2 and neurotoxic phenotype M1, predominant during chronic neuroinflammation.

Endocannabinoid system provides an attractive target to control the balance between microglial phenotypes.

Anandamide as an immune modulator in the central nervous system acts via not only cannabinoid receptors (CB1 and CB2) but also other targets (e.g., GPR18/GPR55).

In summary, we showed that the endocannabinoid system plays a crucial role in the management of neuroinflammation by dampening the activation of an M1 phenotype. This effect was primarily controlled by the CB2 receptor, although functional cross talk with GPR18/GPR55 may occur.”

http://www.ncbi.nlm.nih.gov/pubmed/26090232

Endocannabinoids drive the acquisition of an alternative phenotype in microglia.

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“The ability of microglia to acquire diverse states of activation, or phenotypes, reflects different features that are determinant for their contribution to homeostasis in the adult CNS, and their activity in neuroinflammation, repair or immunomodulation.

Despite the widely reported immunomodulatory effects of cannabinoids in both the peripheral immune system and the CNS, less is known about how the endocannabinoid signaling system (eCBSS) influence the microglial phenotype.

The general aim of the present study was to investigate the role of endocannabinoids in microglia polarization by using microglia cell cultures.

We show that alternative microglia (M2a) and acquired deactivated microglia (M2c) exhibit changes in the eCB machinery that favor the selective synthesis of 2-AG and AEA, respectively.

Once released, these eCBs might be able to act through CB1 and/or CB2 receptors in order to influence the acquisition of an M2 phenotype.

We present three lines of evidence that the eCBSS is critical for the acquisition of the M2 phenotype: (i) M2 polarization occurs on exposure to the two main endocannabinoids 2-AG and AEA in microglia cultures; (ii)cannabinoid receptor antagonists block M2 polarization; and, (iii) M2 polarization is dampened in microglia from CB2 receptor knockout mice.

Taken together, these results indicate the interest of eCBSS for the regulation of microglial activation in normal and pathological conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/26086345

Coadministration of indomethacin and minocycline attenuates established paclitaxel-induced neuropathic thermal hyperalgesia: Involvement of cannabinoid CB1 receptors.

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“Taxanes such as paclitaxel, which are chemotherapeutic drugs, cause dose-dependent painful neuropathy in some patients.

We investigated whether coadministration of minocycline and indomethacin produces antinociceptive effects in mice with paclitaxel-induced neuropathic thermal hyperalgesia and if the cannabinoid system is involved…

In conclusion our results indicate that coadministration of minocycline and indomethacin abrogates established paclitaxel-induced neuropathic thermal hyperalgesia in mice, and the potentiation of the antinociceptive effects of this combination involves the cannabinoid system.”