The endocannabinoid-alcohol crosstalk: recent advances on a bi-faceted target.

Clinical and Experimental Pharmacology and Physiology banner

“Increasing evidence focuses on the endocannabinoid system as a relevant player in the induction of aberrant synaptic plasticity and related addictive phenotype following chronic excessive alcohol drinking.

Besides, the endocannabinoid system is implicated in the pathogenesis of alcoholic liver disease.

Interestingly, whereas the involvement of CB1 cannabinoid receptors in alcohol rewarding properties is established, the central and peripheral action of CB2 cannabinoid signalling is still to be elucidated.

This review aims at giving the input to deepen knowledge on the role of the endocannabinoid system, highlighting the advancing evidence that suggests that CB1 and CB2 receptors may play opposite roles in the regulation of both the reinforcing properties of alcohol in the brain and the mechanisms responsible for cell injury and inflammation in the hepatic tissue.

The manipulation of the endocannabinoid system could represent a bi-faceted strategy to counteract alcohol-related dysfunction in central transmission and liver structural and functional disarrangement.”

https://www.ncbi.nlm.nih.gov/pubmed/29770478

https://onlinelibrary.wiley.com/doi/abs/10.1111/1440-1681.12967

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Cannabinoid 1 receptors are expressed in nociceptive primary sensory neurons.

 Neuroscience

“Expression of cannabinoid 1 (CB1) and vanilloid 1 (VR1) receptor proteins was studied in adult, cultured rat dorsal root ganglion neurons. Immunostaining of CB1 receptors alone produced labelling in 57+/-2% of the cultured dorsal root ganglion neurons (n=3 cultures). The area of the labelled cells was between 200 and 800 microm(2) with an average of 527+/-68 microm(2). VR1 immunolabelling revealed immunopositivity in 42+/-6% of the total population of dorsal root ganglion neurons. Cells showing VR1-like immunopositivity had an area between 200 and 600 microm(2). The mean area of the VR1-like immunopositive neurons was 376+/-61 microm(2). Double immunostaining with antisera raised against the CB1 and VR1 receptor proteins, showed a high degree of co-expression between CB1 and VR1 receptors. An average of 82+/-3% of the CB1-like immunopositive cells also showed VR1-like immunoreactivity (n=3 cultures) while 98+/-2% of the VR1-like immunolabelled neurons showed CB1 receptor-like immunostaining (n=3 cultures). Our data suggests that nociceptive primary sensory neurons co-express CB1 and VR1 receptors to a very high degree. We propose that this may provide an anatomical basis for a powerful combination of VR1 mediated excitation and CB1-mediated inhibition of nociceptive responses at central and peripheral terminals of nociceptive primary afferents.”

https://www.ncbi.nlm.nih.gov/pubmed/11036202

https://www.sciencedirect.com/science/article/abs/pii/S0306452200003894

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Possible mechanisms of cannabinoid-induced antinociception in the spinal cord.

European Journal of Pharmacology

“Anandamide is an endogenous ligand at both the inhibitory cannabinoid CB(1) receptor and the excitatory vanilloid receptor 1 (VR1). The CB(1) receptor and vanilloid VR1 receptor are expressed in about 50% and 40% of dorsal root ganglion neurons, respectively. While all vanilloid VR1 receptor-expressing cells belong to the calcitonin gene-related peptide-containing and isolectin B4-binding sub-populations of nociceptive primary sensory neurons, about 80% of the cannabinoid CB(1) receptor-expressing cells belong to those sub-populations. Furthermore, all vanilloid VR1 receptor-expressing cells co-express the cannabinoid CB(1) receptor.

In agreement with these findings, neonatal capsaicin treatment that induces degeneration of capsaicin-sensitive, vanilloid VR1 receptor-expressing, thin, unmyelinated, nociceptive primary afferent fibres significantly reduced the cannabinoid CB(1) receptor immunostaining in the superficial spinal dorsal horn.

Synthetic cannabinoid CB(1) receptor agonists, which do not have affinity at the vanilloid VR1 receptor, and low concentrations of anandamide both reduce the frequency of miniature excitatory postsynaptic currents and electrical stimulation-evoked or capsaicin-induced excitatory postsynaptic currents in substantia gelatinosa cells in the spinal cord without any effect on their amplitude. These effects are blocked by selective cannabinoid CB(1) receptor antagonists. Furthermore, the paired-pulse ratio is increased while the postsynaptic response of substantia gelatinosa neurons induced by alpha-amino-3-hydroxy-5-methylisoxasole-propionic acid (AMPA) in the presence of tetrodotoxin is unchanged following cannabinoid CB(1) receptor activation.

These results strongly suggest that the cannabinoid CB(1) receptor is expressed presynaptically and that the activation of these receptors by synthetic cannabinoid CB(1) receptor agonists or low concentration of anandamide results in inhibition of transmitter release from nociceptive primary sensory neurons. High concentrations of anandamide, on the other hand, increase the frequency of miniature excitatory postsynaptic currents recorded from substantia gelatinosa neurons. This increase is blocked by ruthenium red, suggesting that this effect is mediated through the vanilloid VR1 receptor.

Thus, anandamide at high concentrations can activate the VR1 and produce an opposite, excitatory effect to its inhibitory action produced at low concentrations through cannabinoid CB(1) receptor activation. This “dual”, concentration-dependent effect of anandamide could be an important presynaptic modulatory mechanism in the spinal nociceptive system.”

https://www.ncbi.nlm.nih.gov/pubmed/11698030

https://www.sciencedirect.com/science/article/pii/S0014299901013097?via%3Dihub

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LH-21, A Peripheral Cannabinoid Receptor 1 Antagonist, Exerts Favorable Metabolic Modulation Including Antihypertensive Effect in KKAy Mice by Regulating Inflammatory Cytokines and Adipokines on Adipose Tissue.

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“Patients with obesity are susceptible to hypertension and diabetes. Over-activation of cannabinoid receptor 1 (CB1R) in adipose tissue is proposed in the pathophysiology of metabolic disorders, which led to the metabolic dysfunction of adipose tissue and deregulated production and secretion of adipokines.

In the current study, we determined the impact of LH-21, a representative peripheral CB1R antagonist, on the obesity-accompanied hypertension and explored the modulatory action of LH-21 on the adipose tissue in genetically obese and diabetic KKAy mice.

3-week LH-21 treatment significantly decreased blood pressure with a concomitant reduction in body weight, white adipose tissue (WAT) mass, and a slight loss on food intake in KKAy mice. Meanwhile, glucose handling and dyslipidemia were also markedly ameliorated after treatment. Gene expression of pro-inflammatory cytokines in WAT and the aortae were both attenuated apparently by LH-21, as well the mRNA expression of adipokines (lipocalin-2, leptin) in WAT. Concomitant amelioration on the accumulation of lipocalin-2 was observed in both WAT and aortae. In corresponding with this, serum inflammatory related cytokines (tumor necrosis factor α, IL-6, and CXCL1), and lipocalin-2 and leptin were lowered notably.

Thus according to current results, it can be concluded that the peripheral CB1R antagonist LH-21 is effective in managing the obesity-accompanied hypertension in KKAy mice. These metabolic benefits are closely associated with the regulation on the production and secretion of inflammatory cytokines and adipokines in the WAT, particularly alleviated circulating lipocalin-2 and its accumulation in aortae.”

https://www.ncbi.nlm.nih.gov/pubmed/29731737

https://www.frontiersin.org/articles/10.3389/fendo.2018.00167/full

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Adolescent chronic mild stress alters hippocampal CB1 receptor-mediated excitatory neurotransmission and plasticity

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“Endocannabinoids (eCBS) are involved in the stress response and alterations in eCB signaling may contribute to the etiology of mood disorders.

Exposure to chronic mild stress (CMS), a model of depression, produces downregulation of the CB1 receptor (CB1) in the hippocampus of male rats.

These results effectively demonstrate that CMS significantly alters hippocampal eCB-mediated neurotransmission and synaptic plasticity.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827785/

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Cannabidiol inhibits endocannabinoid signaling in autaptic hippocampal neurons.

Molecular Pharmacology

“Δ9-THC and cannabidiol (CBD) are two main cannabinoid constituents of marijuana and hashish. The pharmacology of Δ9-THC has been extensively studied, while our understanding of the pharmacology of CBD has remained limited, despite excitement in CBD’s potential role in treating certain pediatric epilepsies and its reputation for attenuating some Δ9-THC-induced effects.

It was established early on that CBD binds poorly to the orthosteric site of CB1 or CB2 cannabinoid receptors and its actions were commonly attributed to other non-cannabinoid receptor mechanisms. However, recent evidence suggests that CBD does indeed act at cannabinoid CB1 receptors as a negative allosteric modulator (NAM) of CB1 signaling. By altering the orthosteric signaling of a GPCR, allosteric modulators greatly increase the richness of GPCR pharmacology.

We have recently surveyed candidate CB1 NAMs in autaptic hippocampal neurons, a well-characterized neuronal model of endogenous cannabinoid signaling, and have now tested CBD in this model. We find that while CBD has no direct effect on excitatory transmission it does inhibit two forms of endogenous cannabinoid-mediated retrograde synaptic plasticity: depolarization-induced suppression of excitation (DSE) and metabotropic suppression of excitation (MSE), while not affecting signaling via GABA-B receptors.

These results are consistent with the recently described NAM activity of CBD and suggest interesting possible mechanisms for CBD’s therapeutic actions.”

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Cannabinoid Type 1 Receptors are Upregulated During Acute Activation of Brown Adipose Tissue.

Diabetes

“Activating brown adipose tissue (BAT) could provide a potential approach for the treatment of obesity and metabolic disease in humans.

Obesity is associated with up-regulation of the endocannabinoid system, and blocking the cannabinoid type 1 receptor (CB1R) has been shown to cause weight loss and decrease cardiometabolic risk factors. These effects may partly be mediated via increased BAT metabolism, since there is evidence that CB1R antagonism activates BAT in rodents.

To investigate the significance of CB1R in BAT function, we quantified the density of CB1R in human and rodent BAT using the positron emission tomography (PET) radioligand [18F]FMPEP-d2 , and in parallel measured BAT activation with the glucose analogue [18F]FDG. Activation by cold exposure markedly increased CB1R density and glucose uptake in BAT of lean men. Similarly, β3-receptor agonism increased CB1R density in BAT of rats.

In contrast, overweight men with reduced BAT activity exhibited decreased CB1R in BAT, reflecting impaired endocannabinoid regulation. Image-guided biopsies confirmed CB1R mRNA expression in human BAT. Furthermore, CB1R blockade increased glucose uptake and lipolysis of brown adipocytes.

Our results highlight that CB1Rs are significant for human BAT activity, and the CB1R provide a novel therapeutic target for BAT activation in humans.”

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Pharmacological characterization of the cannabinoid receptor 2 agonist, β-caryophyllene on seizure models in mice.

Seizure - European Journal of Epilepsy Home

“Activation of CB1 receptors, produces anticonvulsant effect accompanied by memory disturbance both in animal seizure tests and in patients with epilepsy.

Few reports considered the role of CB2 receptor on seizure susceptibility and cognitive functions. The aim of the present study was to explore the effect of a selective CB2 receptor agonist β-caryophyllene (BCP) in models of seizures and cognition in mice.

CONCLUSION:

Our results suggest that the CB2 receptor agonists might be clinically useful as an adjunct treatment against seizure spread and status epilepticus and concomitant oxidative stress, neurotoxicity and cognitive impairments.”

https://www.ncbi.nlm.nih.gov/pubmed/29547827

http://www.seizure-journal.com/article/S1059-1311(17)30611-8/fulltext

“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

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Anticonvulsive effects of endocannabinoids; an investigation to determine the role of regulatory components of endocannabinoid metabolism in the Pentylenetetrazol induced tonic- clonic seizures.

Metabolic Brain Disease

“2-Arachidonoylglycerol (2-AG) and anandamide are two major endocannabinoids produced, released and eliminated by metabolic pathways.

Anticonvulsive effect of 2-AG and CB1 receptor is well-established. Herein, we designed to investigate the anticonvulsive influence of key components of the 2-AG and anandamide metabolism.

It seems extracellular accumulation of 2-AG or anandamide has anticonvulsive effect through the CB1 receptor, while intracellular anandamide accumulation is proconvulsive through TRPV1.”

https://www.ncbi.nlm.nih.gov/pubmed/29504066

https://link.springer.com/article/10.1007%2Fs11011-018-0195-5

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The inhibition of CB1 receptor accelerates the onset and development of EAE possibly by regulating microglia/macrophages polarization.

Journal of Neuroimmunology

“Cannabinoid 1 receptor (CB1R) regulates the neuro-inflammatory and neurodegenerative damages of experimental autoimmune encephalomyelitis (EAE) and of multiple sclerosis (MS). The mechanism by which CB1R inhibition exerts inflammatory effects is still unclear. Here, we explored the cellular and molecular mechanisms of CB1R in the treatment of EAE by using a specific and selective CB1R antagonist SR141716A. Our study demonstrated that SR141716A accelerated the clinical onset and development of EAE, accompanied by body weight loss. SR141716A significantly up-regulated the expression of toll like receptor-4 (TLR-4) and nuclear factor-kappaB/p65 (NF-κB/p65) on microglia/macrophages of EAE mice as well as levels of inflammatory factors (TNF-α, IL-1β, IL-6) and chemokines (MCP-1, CX3CL1), accompanied by the shifts of cytokines from Th2 (IL-4, IL-10) to Th1 (IFN-γ)/Th17 (IL-17) in the spinal cords of EAE mice. Similar changes happened on splenic mononuclear cells (MNCs) except chemokine CX3CL1. Consistently, SR141716A promoted BV-2 microglia to release inflammatory factors (TNF-α, IL-1β, IL-6) while inhibited the production of IL-10 and chemokines (MCP-1, CX3CL1). Furthermore, when splenic CD4+ T cells co-cultured with SR141716A-administered BV-2 microglia, the levels of IL-4 and IL-10 were decreased while production of IL-17 and IFN-γ increased significantly. Our research indicated that inhibition of CB1R induced M1 phenotype-Th17 axis changed of microglia/macrophages through TLR-4 and NF-κB/p65 which accelerated the onset and development of EAE. Therefore, CB1R may be a promising target for the treatment of MS/EAE, but its complexity remains to be carefully considered and studied in further clinical application.”

https://www.ncbi.nlm.nih.gov/pubmed/29501084

http://www.jni-journal.com/article/S0165-5728(17)30467-8/fulltext

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