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

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis.

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“The endocannabinoid system comprises receptors (CB1 and CB2 cannabinoid receptors), enzymes (Fatty Acid Amide Hydrolase [FAAH], which synthesizes the endocannabinoid anandamide), as well as the anandamide membrane transporter (AMT).

Importantly, previous experiments have demonstrated that the endocannabinoid system modulates multiple neurobiological functions, including sleep.

For instance, SR141716A (the CB1 cannabinoid receptor antagonist) as well as URB597 (the FAAH inhibitor) increase waking in rats whereas VDM-11 (the blocker of the AMT) enhances sleep in rodents. However, no further evidence is available regarding the neurobiological role of the endocannabinoid system in the homeostatic control of sleep.

Therefore, the aim of the current experiment was to test if SR141716A, URB597 or VDM-11 would modulate the sleep rebound after sleep deprivation. Thus, these compounds were systemically injected (5, 10, 20mg/Kg; ip; separately each one) to rats after prolonged waking. We found that SR141716A and URB597 blocked in dose-dependent fashion the sleep rebound whereas animals treated with VDM-11 displayed sleep rebound during the recovery period.

Complementary, injection after sleep deprivation of either SR141716A or URB597 enhanced dose-dependently the extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, as well as adenosine while VDM-11 caused a decline in contents of these molecules.

These findings suggest that SR141716A or URB597 behave as a potent stimulants since they suppressed the sleep recovery period after prolonged waking.

It can be concluded that elements of the endocannabinoid system, such as the CB1 cannabinoid receptor, FAAH and AMT, modulate the sleep homeostasis after prolonged waking.”

https://www.ncbi.nlm.nih.gov/pubmed/27746343

[The endocannabinoid system and bone].

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“Recent studies suggest an important role for the skeletal endocannabinoid system in the regulation of bone mass in both physiological and pathological conditions. Both major endocannabinoids (anandamid and 2-arachidonoylglycerol), endocannabinoid receptors – CB1-receptor (CB1R) a CB2-receptor (CB2R) and the endocannabinoid metabolizing enzymes are present or expressed in osteoblasts and osteoclasts. Previous studies identified multiple risk and protective variants of CNR2 gene dealing with the relationship to bone density and/or osteoporosis. Selective CB1R/ CB2R-inverse agonists/antagonists and CB2R-inverse agonists/antagonists are candidates for prevention of bone mass loss and combined antiresorptive and anabolic therapy for osteoporosis.”

https://www.ncbi.nlm.nih.gov/pubmed/27734700

Mechanisms of Broad-Spectrum Antiemetic Efficacy of Cannabinoids against Chemotherapy-Induced Acute and Delayed Vomiting.

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“Chemotherapy-induced nausea and vomiting (CINV) is a complex pathophysiological condition and consists of two phases.

The conventional CINV neurotransmitter hypothesis suggests that the immediate phase is mainly due to release of serotonin (5-HT) from the enterochromaffin cells in the gastrointestinal tract (GIT), while the delayed phase is a consequence of release of substance P (SP) in the brainstem. However, more recent findings argue against this simplistic neurotransmitter and anatomical view of CINV.

Revision of the hypothesis advocates a more complex, differential and overlapping involvement of several emetic neurotransmitters/modulators (e.g. dopamine, serotonin, substance P, prostaglandins and related arachidonic acid derived metabolites) in both phases of emesis occurring concomitantly in the brainstem and in the GIT enteric nervous system (ENS).

No single antiemetic is currently available to completely prevent both phases of CINV.

The standard antiemetic regimens include a 5-HT₃ antagonist plus dexamethasone for the prevention of acute emetic phase, combined with an NK1 receptor antagonist (e.g. aprepitant) for the delayed phase. Although NK1 antagonists behave in animals as broad-spectrum antiemetics against different emetogens including cisplatin-induced acute and delayed vomiting, by themselves they are not very effective against CINV in cancer patients.

Cannabinoids such as D⁸-THC also behave as broad-spectrum antiemetics against diverse emetic stimuli as well as being effective against both phases of CINV in animals and patients.

Potential side effects may limit the clinical utility of direct-acting cannabinoid agonists which could be avoided by the use of corresponding indirect-acting agonists.

Cannabinoids (both phyto-derived and synthetic) behave as agonist antiemetics via the activation of cannabinoid CB₁ receptors in both the brainstem and the ENS emetic loci.

An endocannabinoid antiemetic tone may exist since inverse CB₁ agonists (but not the corresponding silent antagonists) cause nausea and vomiting.”

https://www.ncbi.nlm.nih.gov/pubmed/27713384

Dendritic Cell Regulation by Cannabinoid-Based Drugs.

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“Cannabinoid pharmacology has made important advances in recent years after the cannabinoid system was discovered.

Studies in experimental models and in humans have produced promising results using cannabinoid-based drugs for the treatment of obesity and cancer, as well as neuroinflammatory and chronic inflammatory diseases.

Moreover, as we discuss here, additional studies also indicates that these drugs have immunosuppressive and anti-inflammatory properties including modulation of immune cell function.

Thus, manipulation of the endocannabinoid system in vivo may provide novel therapeutic strategies against inflammatory disorders.

At least two types of cannabinoid receptors, cannabinoid 1 and cannabinoid 2 receptors are expressed on immune cells such as dendritic cells (DC). Dendritic cells are recognized for their critical role in initiating and maintaining immune responses.

Therefore, DC are potential targets for cannabinoid-mediated modulation.

Here, we review the effects of cannabinoids on DC and provide some perspective concerning the therapeutic potential of cannabinoids for the treatment of human diseases involving aberrant inflammatory processes.”

https://www.ncbi.nlm.nih.gov/pubmed/27713374

Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3

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“Spinocerebellar ataxia type-3 (SCA-3) is a rare disease but it is the most frequent type within the autosomal dominant inherited ataxias. The disease lacks an effective treatment to alleviate major symptoms and to modify disease progression.

Our recent findings that endocannabinoid receptors and enzymes are significantly altered in the post-mortemcerebellum of patients affected by autosomal-dominant hereditary ataxias suggest that targeting the endocannabinoid signaling system may be a promising therapeutic option.

Our goal was to investigate the status of the endocannabinoid signaling system in a transgenic mouse model of SCA-3, in the two CNS structures most affected in this disease –cerebellum and brainstem-.

These animals exhibited progressive motor incoordination, imbalance, abnormal gait, muscle weakness, and dystonia, in parallel to reduced in vivobrain glucose metabolism, deterioration of specific neuron subsets located in the dentate nucleus and pontine nuclei, small changes in microglial morphology, and reduction in glial glutamate transporters.

Concerning the endocannabinoid signaling, our data indicated no changes in CB2 receptors. By contrast, CB1 receptors increased in the Purkinje cell layer, in particular in terminals of basket cells, but they were reduced in the dentate nucleus.

We also measured the levels of endocannabinoid lipids and found reductions in anandamide and oleanolamideoyleth in the brainstem. These changes correlated with an increase in the FAAH enzyme in the brainstem, which also occurred in some cerebellar areas, whereas other endocannabinoid-related enzymes were not altered.

Collectively, our results in SCA-3 mutant mice confirm a possible dysregulation in the endocannabinoid system in the most important brain structures affected in this type of ataxia, suggesting that a pharmacological manipulation addressed to correct these changes could be a promising option in SCA-3.”

http://www.sciencedirect.com/science/article/pii/S0306452216305012

Brain CB₂ Receptors: Implications for Neuropsychiatric Disorders.

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“Although previously thought of as the peripheral cannabinoid receptor, it is now accepted that the CB₂ receptor is expressed in the central nervous system on microglia, astrocytes and subpopulations of neurons.

Expression of the CB₂ receptor in the brain is significantly lower than that of the CB₁ receptor. Conflicting findings have been reported on the neurological effects of pharmacological agents targeting the CB₂ receptor under normal conditions.

Under inflammatory conditions, CB₂ receptor expression in the brain is enhanced and CB2 receptor agonists exhibit potent anti-inflammatory effects. These findings have prompted research into the CB₂ receptor as a possible target for the treatment of neuroinflammatory and neurodegenerative disorders.

Neuroinflammatory alterations are also associated with neuropsychiatric disorders and polymorphisms in the CB₂ gene have been reported in depression, eating disorders and schizophrenia. This review will examine the evidence to date for a role of brain CB₂ receptors in neuropsychiatric disorders.”

 https://www.ncbi.nlm.nih.gov/pubmed/27713365

Vascular Dysfunction in a Transgenic Model of Alzheimer’s Disease: Effects of CB1R and CB2R Cannabinoid Agonists.

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“There is evidence of altered vascular function, including cerebrovascular, in Alzheimer’s disease (AD) and transgenic models of the disease.

Indeed vasoconstrictor responses are increased, while vasodilation is reduced in both conditions. β-Amyloid (Aβ) appears to be responsible, at least in part, of alterations in vascular function.

Cannabinoids, neuroprotective and anti-inflammatory agents, induce vasodilation both in vivo and in vitro.

We have demonstrated a beneficial effect of cannabinoids in models of AD by preventing glial activation.

In this work we have studied the effects of these compounds on vessel density in amyloid precursor protein (APP) transgenic mice, line 2576, and on altered vascular responses in aortae isolated ring.

In summary, we have confirmed and extended the existence of altered vascular responses in Tg APP mice.

Moreover, our results suggest that treatment with cannabinoids may ameliorate the vascular responses in AD-type pathology.”

 https://www.ncbi.nlm.nih.gov/pubmed/27695396

β-caryophyllene and β-caryophyllene oxide-natural compounds of anticancer and analgesic properties.

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Cancer Biology & Medicine

“Natural bicyclic sesquiterpenes, β-caryophyllene (BCP) and β-caryophyllene oxide (BCPO), are present in a large number of plants worldwide.

Both BCP and BCPO (BCP(O)) possess significant anticancer activities, affecting growth and proliferation of numerous cancer cells.

In addition, both compounds potentiate the classical drug efficacy by augmenting their concentrations inside the cells.

BCP is a phytocannabinoid with strong affinity to cannabinoid receptor type 2 (CB2 ), but not cannabinoid receptor type 1 (CB1 ). In opposite, BCP oxidation derivative, BCPO, does not exhibit CB1/2 binding, thus the mechanism of its action is not related to endocannabinoid system (ECS) machinery.

It is known that BCPO alters several key pathways for cancer development, such as mitogen-activated protein kinase (MAPK), PI3K/AKT/mTOR/S6K1 and STAT3 pathways. In addition, treatment with this compound reduces the expression of procancer genes/proteins, while increases the levels of those with proapoptotic properties.

The selective activation of CB2 may be considered a novel strategy in pain treatment, devoid of psychoactive side effects associated with CB1 stimulation. Thus, BCP as selective CB2 activator may be taken into account as potential natural analgesic drug.

Moreover, due to the fact that chronic pain is often an element of cancer disease, the double activity of BCP, anticancer and analgesic, as well as its beneficial influence on the efficacy of classical chemotherapeutics, is particularly valuable in oncology.

This review is focused on anticancer and analgesic activities of BCP and BCPO, the mechanisms of their actions, and potential therapeutic utility.”

https://www.ncbi.nlm.nih.gov/pubmed/27696789

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”  http://www.ncbi.nlm.nih.gov/pubmed/23138934

Anandamide Suppresses Proinflammatory T Cell Responses In Vitro through Type-1 Cannabinoid Receptor-Mediated mTOR Inhibition in Human Keratinocytes.

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“The endocannabinoid system comprises cannabinoid receptors 1 and 2 (CB1 and CB2), their endogenous ligands, anandamide (AEA) and 2-arachidonoylglycerol, and metabolic enzymes of these ligands.

The endocannabinoid system has recently been implicated in the regulation of various pathophysiological processes of the skin that include immune competence and/or tolerance of keratinocytes, the disruption of which might promote the development of skin diseases.

Recent evidence showed that CB1 in keratinocytes limits the secretion of proinflammatory chemokines, suggesting that this receptor might also regulate T cell dependent inflammatory diseases of the skin.

In this article, we sought to investigate the cytokine profile of IFN-γ-activated keratinocytes, and found that CB1 activation by AEA suppressed production and release of signature TH1- and TH17-polarizing cytokines, IL-12 and IL-23, respectively. We also set up cocultures between a conditioned medium of treated keratinocytes and naive T cells to disclose the molecular details that regulate the activation of highly proinflammatory TH1 and TH17 cells.

AEA-treated keratinocytes showed reduced an induction of IFN-γ-producing TH1 and IL-17-producing TH17 cells, and these effects were reverted by pharmacological inhibition of CB1.

Further analyses identified mammalian target of rapamycin as a proinflammatory signaling pathway regulated by CB1, able to promote either IL-12 and IL-23 release from keratinocytes or TH1 and TH17 polarization.

Taken together, these findings demonstrate that AEA suppresses highly pathogenic T cell subsets through CB1-mediated mammalian target of rapamycin inhibition in human keratinocytes.

Thus, it can be speculated that the latter pathway might be beneficial to the physiological function of the skin, and can be targeted toward inflammation-related skin diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/27694494

Targeting Cannabinoid CB2 Receptors in the Central Nervous System. Medicinal Chemistry Approaches with Focus on Neurodegenerative Disorders.

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“Endocannabinoids activate two types of specific G-protein-coupled receptors (GPCRs), namely cannabinoid CB1 and CB2. Contrary to the psychotropic actions of agonists of CB1 receptors, and serious side effects of the selective antagonists of this receptor, drugs acting on CB2 receptors appear as promising drugs to combat CNS diseases (Parkinson’s disease, Huntington’s chorea, cerebellar ataxia, amyotrohic lateral sclerosis). Differential localization of CB2 receptors in neural cell types and upregulation in neuroinflammation are keys to understand the therapeutic potential in inter alia diseases that imply progressive neurodegeneration. Medicinal chemistry approaches are now engaged to develop imaging tools to map receptors in the living human brain, to develop more efficacious agonists, and to investigate the possibility to develop allosteric modulators.”

 https://www.ncbi.nlm.nih.gov/pubmed/27679556