Modulation of the endocannabinoid system by sex hormones: Implications for Posttraumatic Stress Disorder.

Neuroscience & Biobehavioral Reviews

“The endocannabinoid system is an increasingly recognised pharmacological target for treating stress and anxiety disorders, including post-traumatic stress disorder (PTSD). Recent preclinical developments have implicated the endocannabinoid system in stress responses, emotional memories and fear extinction, all critical to PTSD aetiology. However, preclinical research in endocannabinoid biology has neglected the influential role of sex hormone differences on PTSD symptomology, which is particularly important given that PTSD is twice as common in women as in men. In this review, we compile and consider the evidence that the endocannabinoid system is influenced by ovarian hormones, with application to stress disorders such as PTSD. It is clear that therapeutic modulation of the endocannabinoid system needs to be approached with awareness of ovarian hormonal influences, and knowledge of these influences may enhance treatment outcomes for female PTSD populations.”

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Integrating endocannabinoid signaling in the regulation of anxiety and depression

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“Brain endogenous cannabinoid (eCB) signaling seems to harmonize appropriate behavioral responses, which are essential for the organism’s long-term viability and homeostasis. Dysregulation of eCB signaling contributes to negative emotional states and increased stress responses. An understanding of the underlying neural cell populations and neural circuit regulation will enable the development of therapeutic strategies to mitigate behavioral maladaptation and provide insight into the influence of eCB on the neural circuits involved in anxiety and depression. This review focuses on recent evidence that has added a new layer of complexity to the idea of targeting the eCB system for therapeutic benefits in neuropsychiatric disease and on the future research direction of neural circuit modulation.” 

https://www.nature.com/articles/s41401-018-0051-5

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Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity.

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“Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses.

Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD.

We examined the effects of exposure to a severe footshock followed by situational reminders (SRs) on extinction, plasticity, and endocannabinoid (eCB) content and activity in the hippocampal CA1 area and basolateral amygdala (BLA).

The findings suggest that targeting the eCB system before extinction may be beneficial in fear memory attenuation and these effects may involve metaplasticity in the CA1 and BLA.”

https://www.ncbi.nlm.nih.gov/pubmed/29977073

https://www.nature.com/articles/s41386-018-0135-4

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Brain endocannabinoid signaling exhibits remarkable complexity.

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“The endocannabinoid (eCB) signaling system is one of the most extensive of the mammalian brain. Despite the involvement of only few specific ligands and receptors, the system encompasses a vast diversity of triggered mechanisms and driven effects. It mediates a wide range of phenomena, including the regulation of transmitter release, neural excitability, synaptic plasticity, impulse spread, long-term neuronal potentiation, neurogenesis, cell death, lineage segregation, cell migration, inflammation, oxidative stress, nociception and the sleep cycle. It is also known to be involved in the processes of learning and memory formation. This extensive scope of action is attained by combining numerous variables. In a properly functioning brain, the correlations of these variables are kept in a strictly controlled balance; however, this balance is disrupted in many pathological conditions. However, while this balance is known to be disrupted by drugs in the case of addicts, the stimuli and mechanisms influencing the neurodegenerating brain remain elusive. This review examines the multiple factors and phenomena affecting the eCB signaling system in the brain. It evaluates techniques of controlling the eCB system to identify the obstacles in their applications and highlights the crucial interdependent variables that may influence biomedical research outcomes.”

https://www.ncbi.nlm.nih.gov/pubmed/29953913

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Cannabigerol Action at Cannabinoid CB1 and CB2 Receptors and at CB1–CB2 Heteroreceptor Complexes

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“Cannabigerol (CBG) is one of the major phytocannabinoids present in Cannabis sativa L. that is attracting pharmacological interest because it is non-psychotropic and is abundant in some industrial hemp varieties.

The aim of this work was to investigate in parallel the binding properties of CBG to cannabinoid CB1 (CB1R) and CB2 (CB2R) receptors and the effects of the compound on agonist activation of those receptors and of CB1–CB2 heteroreceptor complexes.

The results indicate that CBG is indeed effective as regulator of endocannabinoid signaling.

In conclusion, the results presented in this study reveal that the non-psychotropic phytocannabinoid, CBG, may exert beneficial actions with therapeutic potential via cannabinoid receptors.”

https://www.frontiersin.org/articles/10.3389/fphar.2018.00632/full

“International Multi-Centre Collaboration Reveals that Cannabigerol Acts Directly on Cannabinoid Receptors CB1 and CB2” https://www.prnewswire.com/news-releases/international-multi-centre-collaboration-reveals-that-cannabigerol-acts-directly-on-cannabinoid-receptors-cb1-and-cb2-300671024.html

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Inhibition of endocannabinoid degradation rectifies motivational and dopaminergic deficits in the Q175 mouse model of Huntington’s disease.

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“Prominent motor deficits (e.g., chorea) that typify Huntington’s disease (HD) arise following a prolonged prodromal stage characterized by psychiatric disturbances. Apathy, a disorder of motivation characterized by diminished goal-directed behavior, is one of the earliest and most common psychiatric symptoms in HD, but the underlying neurobiology is unclear and treatment options are limited.

Alterations in the endocannabinoid (eCB) and dopamine systems represent prominent pathophysiological markers in HD that-similar to motivational deficits-present early and decline across disease progression. Whether changes in dopamine and eCB systems are associated with specific behavioral impairments in HD and whether these deficits are amenable to viable treatments is unknown.

Here, we show that dopaminergic encoding of effortful drive progressively declines with age in an HD mouse model, and is restored by elevating tissue levels of the eCB 2-arachidonoylglycerol (2-AG) through targeted inhibition of its enzymatic degradation.

This work supports aberrant dopaminergic encoding of reward as a neurobiological correlate of apathy in HD, and indicates that cannabinoid receptor-based therapies may benefit neuropsychiatric care for HD.”

https://www.ncbi.nlm.nih.gov/pubmed/29925886

https://www.nature.com/articles/s41386-018-0107-8

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The Role of Cannabinoids in the Setting of Cirrhosis.

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“Although the mortality rates of cirrhosis are underestimated, its socioeconomic burden has demonstrated a significant global impact. Cirrhosis is defined by the disruption of normal liver architecture after years of chronic insult by different etiologies. Treatment modalities are recommended primarily in decompensated cirrhosis and specifically tailored to the different manifestations of hepatic decompensation. Antifibrogenic therapies are within an active area of investigation.

The endocannabinoid system has been shown to play a role in liver disease, and cirrhosis specifically, with intriguing possible therapeutic benefits. The endocannabinoid system comprises cannabinoid receptors 1 (CB1) and cannabinoid receptor 2 (CB2) and their ligands, endocannabinoids and exocannabinoids.

CB1 activation enhances fibrogenesis, whereas CB2 activation counteracts progression to fibrosis. Conversely, deletion of CB1 is associated with an improvement of hepatic fibrosis and steatosis, and deletion of CB2 results in increased collagen deposition, steatosis, and enhanced inflammation.

CB1 antagonism has also demonstrated vascular effects in patients with cirrhosis, causing an increase in arterial pressure and vascular resistance as well as a decrease in mesenteric blood flow and portal pressure, thereby preventing ascites. In mice with hepatic encephalopathy, CB1 blockade and activation of CB2 demonstrated improved neurologic score and cognitive function.

Endocannabinoids, themselves also have mechanistic roles in cirrhosis. Arachidonoyl ethanolamide (AEA) exhibits antifibrogenic properties by inhibition of HSC proliferation and induction of necrotic death. AEA induces mesenteric vasodilation and hypotension via CB1 induction. 2-arachidonoyl glycerol (2-AG) is a fibrogenic mediator independent of CB receptors, but in higher doses induces apoptosis of HSCs, which may actually show antifibrotic properties. 2-AG has also demonstrated growth-inhibitory and cytotoxic effects.

The exocannabinoid, THC, suppresses proliferation of hepatic myofibroblasts and stellate cells and induces apoptosis, which may reveal antifibrotic and hepatoprotective mechanisms. Thus, several components of the endocannabinoid system have therapeutic potential in cirrhosis.”

https://www.ncbi.nlm.nih.gov/pubmed/29890719

http://www.mdpi.com/2305-6320/5/2/52

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Ischemia/Reperfusion Model Impairs Endocannabinoid Signaling and Na+/K+ ATPase Expression and Activity in Kidney Proximal Tubule Cells.

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“LLC-PK1 cells, an immortalized epithelial cell line derived from pig renal proximal tubules, express all the major players of the endocannabinoid system (ECS) such as CB1, CB2 and TRPV1 receptor, as well as the main enzymes involved in the biosynthesis and degradation of the major endocannabinoids named 2-arachidonoylglycerol, 2-AG and anandamide, AEA.

Here we investigated whether the damages caused by ischemic insult either in vitro using LLC-PK1 cells exposed to antimycin A (an inductor of ATP-depletion) or in vivo using Wistar rats in a classic renal ischemia and reperfusion (IR) protocol, lead to changes in AEA and 2-AG levels, as well as altered expression of genes from the main enzymes involved in the regulation of the ECS.

Our data show that the mRNA levels of CB1 receptor gene were downregulated, while the transcript levels of monoacylglycerol lipase (MAGL), the main 2-AG degradative enzyme, are upregulated in LLC-PK1 cells after IR model. Accordingly, IR was accompanied by a significant reduction in the levels of 2-AG and AEA, as well as of the two endocannabinoid related molecules, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in LLC-PK1 cells. In kidney cortex homogenates, the AEA levels were selectively significantly decreased. In addition, we found that both the in vitro and in vivo model of IR caused a reduction in the expression and activity of the Na+/K+ATPase. These changes were reversed by the CB1/CB2 agonist WIN55,212, in a CB1-receptor dependent manner on LLC-PK1 IR model.

In conclusion, the ECS and Na+/K+ ATPase are down-regulated following IR model in LLC-PK1 cells and rat kidney. We suggest that CB1 agonists might represent a potential strategy to reverse the consequences of IR injury in kidney tissues.”

https://www.ncbi.nlm.nih.gov/pubmed/29890144

https://www.sciencedirect.com/science/article/pii/S0006295218302132

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The relationship of endocannabinoidome lipid mediators with pain and psychological stress in women with fibromyalgia – a case control study.

“Characterized by chronic widespread pain, generalized hyperalgesia, and psychological stress fibromyalgia (FM) is difficult to diagnose and lacks effective treatments.

The endocannabinoids – arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG), and the related oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) – are endogenous lipid mediators with analgesic and anti-inflammatory characteristics, in company with psychological modulating properties (e.g., stress and anxiety), and are included in a new emerging “ome”, the endocannabinoidome.

This case -control study compared the concentration differences of AEA, OEA, PEA, SEA, and 2-AG in 104 women with FM and 116 healthy controls (CON). All participants OEArated their pain, anxiety, depression, and current health status. The relationships between the lipid concentrations and the clinical assessments were investigated using powerful multivariate data analysis and traditional bivariate statistics. The concentrations of OEA, PEA, SEA, and 2-AG were significantly higher in FM than in CON; significance remained for OEA and SEA after controlling for BMI and age. 2-AG correlated positively with FM duration and BMI, and to some extent negatively with pain, anxiety, depression, and health status. In FM, AEA correlated positively with depression ratings.

The elevated circulating levels of endocannabinoidome lipids suggest that these lipids play a role in the complex pathophysiology of FM and might be signs of ongoing low-grade inflammation in FM. Although the investigated lipids are significantly altered in FM their biological roles are uncertain with respect to the clinical manifestations of FM. Thus, plasma lipids alone are not good biomarkers for FM.

PERSPECTIVE:

This study reports about elevated plasma levels of endocannabinoidome lipid mediators in FM. The lipids suitability to work as biomarkers for FM in the clinic were low, however their altered levels indicate that a metabolic asymmetry is ongoing in FM, which could serve as basis during explorative FM pain management.”

https://www.ncbi.nlm.nih.gov/pubmed/29885369

https://www.jpain.org/article/S1526-5900(18)30197-4/fulltext

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Cannabinoid receptor type 1 in the brain regulates the affective component of visceral pain in mice.

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“Endocannabinoids acting through cannabinoid receptor type 1 (CB1) are major modulators of peripheral somatic and visceral nociception. Although only partially studied, some evidence suggests a particular role of CB1 within the brain in nociceptive processes.

As the endocannabinoid system regulates affect and emotional behaviors, we hypothesized that cerebral CB1 influences affective processing of visceral pain-related behaviors in laboratory animals.

To study nocifensive responses modulated by supraspinal CB1, we used conditional knock-out mice lacking CB1 either in cortical glutamatergic neurons (Glu-CB1-KO), or in forebrain GABAergic neurons (GABA-CB1-KO), or in principle neurons of the forebrain (CaMK-CB1-KO). These mutant mice and mice treated with the CB1 antagonist SR141716 were tested for different pain-related behaviors. In an acetic acid-induced abdominal constriction test, supraspinal CB1 deletions did not affect nocifensive responses. In the cerulein-model of acute pancreatitis, mechanical allodynia or hyperalgesia were not changed, but Glu-CB1- and CaMK-CB1-KO mice showed significantly increased facial grimacing scores indicating increased affective responses to this noxious visceral stimulus. Similarly, these brain-specific CB1 KO mice also showed significantly changed thermal nociception in a hot-plate test.

These results reveal a novel, and important role of CB1 expressed by cortical glutamatergic neurons in the affective component of visceral nociception.”

https://www.ncbi.nlm.nih.gov/pubmed/29885522

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