Tag Archives: endocannabinoid system

The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings.

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“Post-Traumatic Stress Disorder (PTSD) is a psychiatric chronic disease developing in individuals after the experience of an intense and life-threatening traumatic event. The post-traumatic symptomatology encompasses alterations in memory processes, mood, anxiety and arousal.

There is now consensus in considering the disease as an aberrant adaptation to traumatic stress. Pharmacological research, aimed at the discovery of new potential effective treatments, has lately directed its attention towards the “so-called” cognitive enhancers. This class of substances, by modulating cognitive processes involved in the development and/or persistence of the post-traumatic symptomatology, could be of great help in improving the outcome of psychotherapies and patients’ prognosis.

In this perspective, drugs acting on the endocannabinoid system are receiving great attention due to their dual ability to modulate memory processes on one hand, and to reduce anxiety and depression on the other.

The purpose of the present review is to offer a thorough overview of both animal and human studies investigating the effects of cannabinoids on memory processes.

First, we will briefly describe the characteristics of the endocannabinoid system and the most commonly used animal models of learning and memory. Then, studies investigating cannabinoid modulatory influences on memory consolidation, retrieval and extinction will be separately presented, and the potential benefits associated with each approach will be discussed.

In the final section, we will review literature data reporting beneficial effects of cannabinoid drugs in PTSD patients.”

http://www.ncbi.nlm.nih.gov/pubmed/27456243

Refractory trigeminal neuralgia responsive to nabiximols in a patient with multiple sclerosis.

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“Nabiximols is a cannabinoid compound approved for the treatment of multiple sclerosis (MS)-related spasticity.

However, additional symptoms, such as pain, urinary urgency and sleep disturbance, may benefit from treatment.

CASE REPORT:

The present report describes a patient with secondary progressive MS and severe lower limbs spasticity who was started on treatment with nabiximols. The patient also suffered from trigeminal neuralgia, which he was not treating due to inefficacy or side effects of all previously tried medications. After nabiximols initiation the patient experienced a marked benefit on trigeminal neuralgia, which completely resolved, while spasticity responded only partially to treatment.

CONCLUSION:

Nabiximols mechanism of action is based on the interaction with CB1 and CB2 receptors, which are expressed by central nervous system neurons and are known to modulate pain among other effects. The present case indicates that nabiximols and other cannabinoids need to be further tested for the treatment of trigeminal neuralgia.”

http://www.ncbi.nlm.nih.gov/pubmed/27456876

“Therapeutic potential of cannabinoids in trigeminal neuralgia. Considering the pronounced antinociceptive effects produced by cannabinoids, they may be a promising therapeutic approach for the clinical management of trigeminal neuralgia.”  http://www.ncbi.nlm.nih.gov/pubmed/15578967

Blockade of Cannabinoid CB1 receptor attenuates the acquisition of morphine-induced conditioned place preference along with a downregulation of ERK, CREB phosphorylation, and BDNF expression in the nucleus accumbens and hippocampus.

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“Cannabinoid CB1 receptor (CB1R) is highly expressed in the mesocorticolimbic system and associated with drug craving and relapse.

Clinical trials suggest that CB1R antagonists may represent new therapies for drug addiction.

Collectively, these findings demonstrate that 1) Repeated morphine with context exposures but not merely the pharmacological effects of morphine increased CB1R expression both in the NAc and hippocampus. 2) CB1R antagonist mediated blockade of ERK-CREB-BDNF signaling activation in the NAc and hippocampus may be an important mechanism underlying the attenuation of morphine CPP.”

http://www.ncbi.nlm.nih.gov/pubmed/27461790

Deficient Adolescent Social Behavior Following Early-Life Inflammation is Ameliorated by Augmentation of Anandamide Signaling.

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“Early-life inflammation has been shown to exert profound effects on brain development and behavior, including altered emotional behavior, stress responsivity and neurochemical/neuropeptide receptor expression and function.

The current study extends this research by examining the impact of inflammation, triggered with the bacterial compound lipopolysaccharide (LPS) on postnatal day (P) 14, on social behavior during adolescence.

We investigate the role that the endocannabinoid (eCB) system plays in sociability after early-life LPS.

These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that inhibition of FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.”

http://www.ncbi.nlm.nih.gov/pubmed/27453335

The CB1 Antagonist, SR141716A, Is Protective in Permanent Photothrombotic Cerebral Ischemia.

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“Modulation of the endocannabinoid system has been shown to have a significant impact on outcomes in animal models of stroke.

We have previously reported a protective effect of the CB1 antagonist, SR141716A, in a transient reperfusion mouse model of cerebral ischemia. This protective effect was in part mediated by activation of the 5HT1A receptor.

Here we have examined its effect in a mouse model of permanent ischemia induced by photoinjury.

The CB1 antagonist was found to be protective in this model.

As was the case following transient ischemia reperfusion, SR141716A (5mg/kg) resulted in smaller infarct fractions and stroke volumes when utilized both as a pretreatment and as a post-treatment. In contrast to the effect in a transient ischemia model, the pretreatment effect did not depend on the 5HT1A receptor.

Neurological function correlated favorably to the reduction in stroke size when SR141716A was given as a pretreatment.

With the incidence of stroke predicted to rise in parallel with an ever aging population, understanding mechanisms underlying ischemia and therapeutics remains a paramount goal of research.”

http://www.ncbi.nlm.nih.gov/pubmed/27453059

Crucial Roles of the Endocannabinoid 2-Arachidonoylglycerol in the Suppression of Epileptic Seizures.

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“Endocannabinoid signaling is considered to suppress excessive excitability of neural circuits and to protect the brain from seizures. However, the precise mechanisms of this effect are poorly understood.

Here, we report that 2-arachidonoylglycerol (2-AG), one of the two major endocannabinoids, is crucial for suppressing seizures.

We found that kainate-induced seizures in mice lacking the 2-AG synthesizing enzyme, diacylglycerol lipase α, were much more severe compared with those in cannabinoid CB1 receptor knockout mice and were comparable to those in mice lacking both CB1– and CB2-receptor-mediated signaling.

In the dentate gyrus, 2-AG suppressed excitatory input around the inner and middle molecular layers through CB1 and presumably CB2 receptors, respectively.

This 2-AG-mediated suppression contributed to decreased granule cell excitability and the dampening of seizures. Furthermore, lack of 2-AG signaling enhanced kindling epileptogenesis and spontaneous seizures after kainate-induced status epilepticus.

These results highlight critical roles of 2-AG signaling in the suppression of epileptic seizures.”

http://www.ncbi.nlm.nih.gov/pubmed/27452464

Peripheral interactions between cannabinoid and opioid receptor agonists in a model of inflammatory mechanical hyperalgesia.

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“Activation of opioid and cannabinoid receptors expressed in nociceptors induces effective antihyperalgesia.

In this study, we examined whether combinations of opioid and cannabinoid receptor agonists directed at the injured site would enhance therapeutic effectiveness.

Our findings showed that MOR and CB1 agonists directed at the inflamed site effectively attenuate mechanical hyperalgesia when administered individually, but exert opposing effects when administered together.

The antagonistic interactions between the two classes of drugs at the inflamed site suggest distinct mechanisms unique to peripheral nociceptors or inflamed tissue, and therefore require further studies to investigate whether the therapeutic utility of the combined drug treatments in chronic pain conditions can be optimized.”

http://www.ncbi.nlm.nih.gov/pubmed/27450703

A study of cannabinoid-1 receptors during the early phase of excitotoxic damage to rat spinal locomotor networks in vitro.

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“Endocannabinoids acting on cannabinoid-1 receptors (CB1Rs) are proposed to protect brain and spinal neurons from excitotoxic damage.

The ability to recover from spinal cord injury (SCI), in which excitotoxicity is a major player, is usually investigated at late times after modulation of CB1Rs whose role in the early phases of SCI remains unclear.

Using the rat spinal cord in vitro as a model for studying SCI initial pathophysiology, we investigated if agonists or antagonists of CB1Rs might affect SCI induced by the excitotoxic agent kainate (KA) within 24 h from a transient (1 h) application of this glutamate agonist.

The present data indicate that the early phases of excitotoxic SCI could not be arrested by pharmacologically exploiting the endocannabinoid system, consistent with the notion that AEA and its derivatives are more useful to treat late SCI phases.”

http://www.ncbi.nlm.nih.gov/pubmed/27450568

Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharide-induced nitric oxide release in astrocyte cultures.

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“The purpose of this study was to investigate the role of the central cannabinoid receptor (CB(1)) in mediating the actions of the endogenous cannabinoid agonist anandamide and the synthetic cannabinoid CP-55940.

Activation of primary mouse astrocyte cultures by exposure to bacterial lipopolysaccharide (LPS) caused a marked (approximately tenfold) increase in nitric oxide (NO) release.

Coincubation with the cannabinoid agonists anandamide or CP-55940 markedly inhibited release of NO (-12% to -55%).

We also showed that endogenous or synthetic cannabinoids inhibit LPS-induced inducible NO synthase expression (mRNA and protein) in astrocyte cultures.

These results indicate that CB1 receptors may promote antiinflammatory responses in astrocytes.”

http://www.ncbi.nlm.nih.gov/pubmed/11891798

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

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“Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment.

Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects.

Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases.

Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group.

Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis.

Regarding the pharmacodynamics of the hybrid CB1R/iNOS inhibitor, two important principles have emerged from efforts to develop effective antifibrotic therapies. First, antifibrotic treatment strategies could aim to control the primary disease, to inhibit fibrogenic gene expression and signaling, to promote molecular mechanisms involved in fibrosis regression, or a combination of these. Second, with multiple molecular mechanisms and signaling pathways involved in fibrosis, targeting more than one could increase antifibrotic efficacy, and the hybrid CB1R/iNOS inhibitor embodies optimal characteristics on both accounts.

As to the first principle, both the endocannabinoid/CB1R system and iNOS are ideal targets, as they are known to be involved directly in the fibrotic process and also in the conditions predisposing to liver fibrosis, as detailed in the Introduction. An emerging major predisposing factor to liver fibrosis is nonalcoholic fatty liver disease, and CB1R blockade has proven effective in mitigating obesity-related hepatic steatosis in both rodent models and humans. The other two major predisposing factors, alcoholic fatty liver disease and viral hepatitis, also involve increased CB1R activity. Hepatic CB1R expression is induced either by chronic ethanol intake or the hepatitis C virus, and CB1R blockade mitigates alcohol-induced steatosis and inhibits hepatitis C virus production.

The dual targeting of peripheral CB1R and iNOS demonstrated here exemplifies the therapeutic gain obtained by simultaneously hitting more than one molecule, which could then engage distinct as well as convergent cellular pathways. The advantage of such an approach is highlighted by emerging experience with recently developed antifibrotic medications, which indicates that targeting a single pathway has limited effect on fibrotic diseases.

Thus, the approach illustrated by the present study has promise as an effective antifibrotic strategy.”

http://insight.jci.org/articles/view/87336