Interaction between interleukin-1β and type-1 cannabinoid receptor is involved in anxiety-like behavior in experimental autoimmune encephalomyelitis.

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“Mood disorders, including anxiety and depression, are frequently diagnosed in multiple sclerosis (MS) patients, even independently of the disabling symptoms associated with the disease.

Anatomical, biochemical, and pharmacological evidence indicates that type-1 cannabinoid receptor (CB1R) is implicated in the control of emotional behavior and is modulated during inflammatory neurodegenerative diseases such as MS and experimental autoimmune encephalomyelitis (EAE).

We investigated whether CB1R could exert a role in anxiety-like behavior in mice with EAE. We performed behavioral, pharmacological, and electrophysiological experiments to explore the link between central inflammation, mood, and CB1R function in EAE.

Overall, results of the present investigation indicate that synaptic dysfunction linked to CB1R is involved in EAE-related anxiety and motivation-based behavior and contribute to clarify the complex neurobiological mechanisms underlying mood disorders associated to MS.

Collectively, our data contribute to clarify the synaptic and, at least in part, molecular basis of mood disturbances in EAE and, possibly, MS. Understanding the neurobiological underpinning of anxiety-like behavior in EAE mice is of crucial importance to optimize the treatment of mood disturbance in MS and, possibly, other neuroinflammatory diseases.

In this direction, targeting the endocannabinoid system may be a valid therapeutic tool for the treatment of both psychiatric and motor symptoms in MS patients.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009553/

Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model.

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“Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability.

The cognitive deficits in the mouse model for this disorder, the Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mouse, have been restored by different pharmacological approaches, among those the blockade of cannabinoid type 1 (CB1) receptor.

In this regard, our previous study showed that the CB1 receptor antagonist/inverse agonist rimonabant normalized a number of core features in the Fmr1 knockout mouse. Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects.

In this study we show, by using electrophysiological approaches, that low dosages of rimonabant (0.1 mg/kg) manage to normalize metabotropic glutamate receptor dependent long-term depression (mGluR-LTD). In addition, low doses of rimonabant (from 0.01 mg/kg) equally normalized the cognitive deficit in the mouse model of FXS.

These doses of rimonabant were from 30 to 300 times lower than those required to reduce body weight in rodents and to presumably produce adverse effects in humans. Furthermore, NESS0327, a CB1 receptor neutral antagonist, was also effective in preventing the novel object-recognition memory deficit in Fmr1 KO mice.

These data further support targeting CB1 receptors as a relevant therapy for FXS.”

http://www.ncbi.nlm.nih.gov/pubmed/27589806

Activation of cannabinoid CB1 receptor contributes to suppression of spinal nociceptive transmission and inhibition of mechanical hypersensitivity by Aβ-fiber stimulation.

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“Activation of Aβ-fibers is an intrinsic feature of spinal cord stimulation (SCS) pain therapy.

Cannabinoid receptor type 1 (CB1) is important to neuronal plasticity and pain modulation, but its role in SCS-induced pain inhibition remains unclear.

In this study, we showed that CB1 receptors are expressed in both excitatory and inhibitory interneurons in substantia gelatinosa (SG).

Our findings suggest that activation of spinal CB1 receptors may contribute to synaptic depression to high-threshold afferent inputs in SG neurons after electrical stimulation of Aβ-fibers (Aβ-ES) and may be involved in SCS-induced inhibition of spinal nociceptive transmission after nerve injury.”

http://www.ncbi.nlm.nih.gov/pubmed/27589093

Selective modulator of cannabinoid receptor type 2 reduces memory impairment and infarct size during cerebral hypoperfusion and vascular dementia.

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“Vascular dementia is the highly devastating neurodegenerative disorder after Alzheimer’s disease (AD) and mainly found in aged people but the effectual therapeutic target is still not there.

Chronic cerebral hypoperfusion (CCH) has been broadly found in vascular dementia (VaD) patients. CCH is thought to link with neurodegenerative disorders and their subsequent cognitive deteriorate on.

This study has been framed to examine the role of a selective agonist of cannabinoid receptor type 2(CB2); 1-phenylisatin in CCH induced VaD.

These results indicate that 2VO induced CCH in rats, which was attenuated with the treatment of 1-phenylisatin.

Hence, it may be suggested that modulation of cannabinoid receptor may provide benefits in CCH as cognitive impairment and VaD.

Therefore, selective agonists of CB2 receptors may be a potential research target for the alleviation of VaD.”

http://www.ncbi.nlm.nih.gov/pubmed/27586843

Dual-Acting Compounds Targeting Endocannabinoid and Endovanilloid Systems-A Novel Treatment Option for Chronic Pain Management.

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“Compared with acute pain that arises suddenly in response to a specific injury and is usually treatable, chronic pain persists over time, and is often resistant to medical treatment.

Because of the heterogeneity of chronic pain origins, satisfactory therapies for its treatment are lacking, leading to an urgent need for the development of new treatments.

The leading approach in drug design is selective compounds, though they are often less effective and require chronic dosing with many side effects.

Herein, we review novel approaches to drug design for the treatment of chronic pain represented by dual-acting compounds, which operate at more than one biological target.

A number of studies suggest the involvement of the cannabinoid and vanilloid receptors in pain.

Interestingly cannabinoid system is in interrelation with other systems that comprise lipid mediators: prostaglandins, produced by COX enzyme.

Therefore, in the present review, we summarize the role of dual-acting molecules (FAAH/TRPV1 and FAAH/COX-2 inhibitors) that interact with endocannabinoid and endovanillinoid systems and act as analgesics by elevating the endogenously produced endocannabinoids and dampening the production of pro-inflammatory prostaglandins.

The plasticity of the endocannabinoid system (ECS) and the ability of a single chemical entity to exert an activity on two receptor systems has been developed and extensively investigated.

Here, we review up-to-date pharmacological studies on compounds interacting with FAAH enzyme together with TRPV1 receptor or COX-2 enzyme respectively.

Multi-target pharmacological intervention for treating pain may lead to the development of original and efficient treatments.”

http://www.ncbi.nlm.nih.gov/pubmed/27582708

The Influence of the CB1 Receptor Ligands on the Schizophrenia-Like Effects in Mice Induced by MK-801.

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“A growing body of psychiatric research has emerged, focusing on the role of endocannabinoid system in psychiatric disorders.

For example, the endocannabinoid system, via cannabinoid CB (CB1 and CB2) receptors, is able to control the function of many receptors, such as N-methyl-D-aspartate (NMDA) receptors connected strictly with psychosis or other schizophrenia-associated symptoms.

The aim of the present research was to investigate the impact of the CB1 receptor ligands on the symptoms typical for schizophrenia.

The present findings confirm that endocannabinoid system is able to modify a variety of schizophrenia-like responses, including the cognitive disturbances and hyperlocomotion in mice.

Antipsychotic-like effects induced by CB1 receptor antagonist, obtained in our research, confirm the potential effect of CB1 receptor blockade and could have important therapeutic implications on clinical settings, in the future.”

http://www.ncbi.nlm.nih.gov/pubmed/27577742

Peltatoside Isolated from Annona crassiflora Induces Peripheral Antinociception by Activation of the Cannabinoid System.

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“Peltatoside is a natural compound isolated from leaves of Annona crassiflora Mart., a plant widely used in folk medicine.

This substance is an analogue of quercetin, a flavonoid extensively studied because of its diverse biological activities, including analgesic effects. Besides, a previous study suggested, by computer structure analyses, a possible quercetin-CB1 cannabinoid receptor interaction.

Thus, the aim of this work was to assess the antinociceptive effect of peltatoside and analyze the cannabinoid system involvement in this action.

Our results suggest that this natural substance is capable of inducing analgesia through the activation of peripheral CB1 receptors, involving endocannabinoids in this process.”

http://www.ncbi.nlm.nih.gov/pubmed/27574895

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Endocannabinoid mechanism for orofacial antinociception induced by electroacupuncture in acupoint St36 in rats.

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“This study was conducted with the aim of evaluating whether electroacupuncture (EA) at acupoint St36 could produce antinociception through the activation of an endocannabinoid mechanism.

CONCLUSION:

This study demonstrated for the first time that the CB1 cannabinoid receptor participates in the antinociceptive effect induced by EA.”

http://www.ncbi.nlm.nih.gov/pubmed/27573715

Characterization of non-olfactory GPCRs in human sperm with a focus on GPR18.

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“G protein-coupled receptors (GPCRs) transduce external chemical cues into intracellular signals and are involved in a plethora of physiological processes, but knowledge regarding the function of these receptors in spermatozoa is limited. In the present study, we performed RNA-Seq and analyzed the expression of the all GPCRs except olfactory receptors in human spermatozoa. We revealed the expression of up to 223 different GPCR transcripts in human spermatozoa (FPKM > 0.1) and identified GPR18, a newly described cannabinoid receptor, together with GPR137 and GPR135, as one of the three most highly expressed GPCRs. To date, the expression of GPR18 was completely unknown in human spermatozoa. We confirmed GPR18 expression using RT-PCR and immuncytochemistry experiments and localized the GPR18 protein in the midpiece of human spermatozoa. Stimulation of human spermatozoa with the GPR18 ligand N-arachidonoylglycine induced the phosphorylation of 12 protein kinases, some of them are for example known to be involved in the acrosome reaction. In line with this, N-arachidonoylglycine affected the cytoskeleton by changing levels of F-actin and inducing the acrosome reaction in human spermatozoa in a concentration-dependent manner. Our results indicate that GPR18 might be involved in physiological processes of human spermatozoa, suggesting GPR18 to be a potential player in sperm physiology.”

http://www.ncbi.nlm.nih.gov/pubmed/27572937

“Cannabinoid receptor activates spermatozoa”               http://medicalxpress.com/news/2016-08-cannabinoid-receptor-spermatozoa.html

Cannabinoid 2 receptor is a novel anti-inflammatory target in experimental proliferative vitreoretinopathy.

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“Proliferative vitreoretinopathy (PVR) can develop after ocular trauma or inflammation and is a common complication of surgery to correct retinal detachment.

Currently, there are no pharmacological treatments for PVR.

Cannabinoids acting at cannabinoid 2 receptor (CB2R) can decrease inflammation and fibrosis.

The objective of this study was to examine the anti-inflammatory actions of CB2R as a candidate novel therapeutic target in experimental PVR.

In conclusion, our results indicate that intervention at early stage PVR with CB2R agonists reduces ocular inflammation and disease severity.

CB2R may represent a therapeutic target to prevent PVR progression and vision loss.”

http://www.ncbi.nlm.nih.gov/pubmed/27569993