Tag Archives: CB(1) and CB(2) receptors

Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury

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Heart and Circulatory Physiology

“CANNABINOIDS ARE NATURAL and synthetic compounds structurally or pharmacologically related to the constituents of the plant Cannabis sativa or to the endogenous agonists (endocannabinoids) of the cannabinoid CB1 and CB2 receptors.

Cannabidiol (CBD) is a major cannabinoid constituent of Cannabis.

In contrast to tetrahydrocannabinol, CBD binds very weakly to CB1 and CB2 receptors. Contrary to most cannabinoids, CBD does not induce psychoactive or cognitive effects.

CBD has been shown to have anti-inflammatory properties. CBD (together with tetrahydrocannabinol) has been successfully tested in a few preliminary human trials related to autoimmune diseases…

Cannabidiol (CBD) is a major, nonpsychoactive Cannabis constituent with anti-inflammatory activity mediated by enhancing adenosine signaling.

Inasmuch as adenosine receptors are promising pharmaceutical targets for ischemic heart diseases, we tested the effect of CBD on ischemic rat hearts.

Our study shows that CBD induces a substantial in vivo cardioprotective effect from ischemia that is not observed ex vivo.

Inasmuch as CBD has previously been administered to humans without causing side effects, it may represent a promising novel treatment for myocardial ischemia.”

http://ajpheart.physiology.org/content/293/6/H3602

Cannabinoid system as a potential target for drug development in the treatment of cardiovascular disease.

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“Although cannabinoids have been recreationally employed for thousands of years, it was not until the discovery of their specific receptors, in the early nineties, that the molecular basis of cannabinoid activity have began to be understood.

Growing research in this field has demonstrated not only that the action of cannabinoids in mammals is mainly receptor-mediated, but also that endogenous cannabinoids, such as anandamide, are produced, metabolized, and taken up across the cell membrane through a facilitated uptake process.

The exogenous administration of cannabinoids, as well as the manipulation of their endogenous levels have been related to a variety of effects, such as analgesia, (temporary) impairment of cognition and learning, appetite enhancement and peripheral vasodilation.

Hence, the endocannabinoid system, including the CB1 and CB2 receptors, the metabolizing enzyme fatty acid amide hydrolase and the anandamide transporter, is a potential target for the development of novel therapeutic drugs in the treatment of various conditions, such as pain, feeding disorders and vascular disease among others.

Although most of the research in the field of cannabinoids has been focused on their effects in the central nervous system, a growing line of evidence indicates that cannabinoids can also play a major role in the control of physiopathological functions in the cardiovascular system.

In this context, endocannabinoids have been proposed as novel possible hypotensive agents, and have been involved in the hypotension observed in septic shock, acute myocardial infarction and cirrhosis. In addition, a protective role for endocannabinoids has been described in ischemia.”

http://www.ncbi.nlm.nih.gov/pubmed/15320476

[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

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

Involvement of cannabinoid receptors in infrasonic noise-induced neuronal impairment.

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“Excessive exposure to infrasound, a kind of low-frequency but high-intensity sound noise generated by heavy transportations and machineries, can cause vibroacoustic disease which is a progressive and systemic disease, and finally results in the dysfunction of central nervous system.

Our previous studies have demonstrated that glial cell-mediated inflammation may contribute to infrasound-induced neuronal impairment, but the underlying mechanisms are not fully understood.

Here, we show that cannabinoid (CB) receptors may be involved in infrasound-induced neuronal injury.

…our results provide the first evidence that CB receptors may be involved in infrasound-induced neuronal impairment possibly by affecting the release of proinflammatory cytokines.”

http://www.ncbi.nlm.nih.gov/pubmed/26058582

Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2.

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“Here, we show a novel pharmacology for inhibition of human neutrophil migration by endocannabinoids, phytocannabinoids, and related compounds.

This study reveals that certain endogenous lipids, phytocannabinoids, and related ligands are potent inhibitors of human neutrophil migration, and it implicates a novel pharmacological target distinct from cannabinoid CB(1) and CB(2) receptors; this target is antagonized by the endogenous compound N-arachidonoyl l-serine.

Furthermore, our findings have implications for the potential pharmacological manipulation of elements of the endocannabinoid system for the treatment of various inflammatory conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/17965195

A Cannabinoid CB1 Receptor Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with no Psychoactive Effects.

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“The CB1 receptor represents a promising target for the treatment of several disorders including pain-related disease states.

However, therapeutic applications of Δ9-tetrahydrocannabinol (THC) and other CB1 orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB1 receptor function for therapeutic gain with the promise of reduced side effects…

These data suggest that ZCZ011 acts as a CB1 PAM and provide the first proof of principle that CB1 PAMs offer a promising strategy to treat neuropathic and inflammatory pain with minimal or no cannabimimetic side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/26052038

Targeting cannabinoid receptors as a novel approach in the treatment of graft-versus-host disease: evidence from an experimental murine model.

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“Allogeneic hematopoietic cell transplantation (HCT) is widely used to treat patients with life-threatening malignant and nonmalignant hematological diseases. However, allogeneic HCT often is accompanied by severe and lethal complications from graft-versus-host disease (GVHD)…

Cannabinoids, the active ingredients found in Cannabis sativa, have been shown to exhibit a wide range of pharmacological properties. Studies from our laboratory and elsewhere have suggested that cannabinoids exhibit potent anti-inflammatory properties and therefore can be used to treat autoimmune and inflammatory diseases.

Cannabinoids have been shown to inhibit tumor cell growth and angiogenesis, suggesting their potential use in the treatment of gliomas, prostate and breast cancers, and malignancies of immune origin.

Δ9-Tetrahydrocannabinol (THC) is one of the most extensively investigated ingredients found in cannabis. THC activates both CB1 and CB2, thereby mediating both psychotropic and anti-inflammatory properties.

Inasmuch as our previous studies suggested that THC exhibits anti-inflammatory and immunosuppressive properties, we tested the possibility of its use in treating GVHD in a parent → F1 model. We hereby demonstrate for the first time that administration of THC during allogeneic transplantation can significantly suppress GVHD…

Our results demonstrate for the first time that targeting cannabinoid receptors may constitute a novel treatment modality against acute GVHD.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164345/

Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications.

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“Knockout (KO) mice invalidated for the dopamine transporter (DAT) constitute a powerful animal model of neurobiological alterations associated with hyperdopaminergia relevant to schizophrenia and attention-deficit/hyperactivity disorder (ADHD).

CONCLUSIONS:

These data indicate a dysregulated striatal endocannabinoid neurotransmission associated with hyperdopaminergic state.

Restoring endocannabinoid homeostasis in active synapses might constitute an alternative therapeutic strategy for disorders associated with hyperdopaminergia.

In this process, TRPV1 receptors seem to play a key role and represent a novel promising pharmacological target.”

http://www.ncbi.nlm.nih.gov/pubmed/16199010