Tag Archives: CNR1

Common polymorphism in the cannabinoid type 1 receptor gene (CNR1) is associated with microvascular complications in type 2 diabetes.

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“Endocannabinoids exert their biological effects via interaction with G-protein coupled cannabinoid receptors CB1 and CB2. Polymorphisms in the CNR1 gene (encoding CB1 receptor) were previously found to be associated with dyslipidemia and cardiovascular diseases. We investigated a role of the polymorphism in CNR1 gene in type 2 diabetes and its complications…

The novel finding of our study is the association of the G1359A polymorphism with diabetic nephropathy and diabetic retinopathy in patients with T2DM. This polymorphism was also associated with cardiovascular disease in the patient group.”

http://www.ncbi.nlm.nih.gov/pubmed/24075694

Association between a Genetic Variant of Type-1 Cannabinoid Receptor and Inflammatory Neurodegeneration in Multiple Sclerosis

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“Genetic ablation of type-1 cannabinoid receptors (CB1Rs) exacerbates the neurodegenerative damage of experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS)…

Our results demonstrate the biological relevance of the (AAT)n CNR1 repeats in the inflammatory neurodegenerative damage of MS…

In conclusion, our study points to CB1R as an interesting molecular target for preventing neuronal loss and cognitive impairment in MS as well as in other CNS disorders in which inflammation-driven neurodegeneration process play a role.”

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0082848

Involvement of cannabinoid receptors in peripheral and spinal morphine analgesia.

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“The interactions between the cannabinoid and opioid systems for pain modulation are reciprocal. However, the role and the importance of the cannabinoid system in the antinociceptive effects of opioids remain uncertain. We studied these interactions with the goal of highlighting the involvement of the cannabinoid system in morphine-induced analgesia.

In both phases of the formalin test, intra paw and intrathecal morphine produced similar antinociceptive effects in C57BL/6, cannabinoid type 1 and type 2 receptor wildtype (respectively cnr1WT and cnr2WT) mice. In cnr1 and cnr2 knockout (KO) mice, at the dose used the antinociceptive effect of intra paw morphine in the inflammatory phase of the formalin test was decreased by 87% and 76%, respectively. Similarly, the antinociceptive effect of 0.1 μg spinal morphine in the inflammatory phase was abolished in cnr1KO mice and decreased by 90% in cnr2KO mice. Interestingly, the antinociceptive effect of morphine in the acute phase of the formalin test was only reduced in cnr1KO mice. Notably, systemic morphine administration produced similar analgesia in all genotypes, in both the formalin and the hot water immersion tail flick tests.

Because the pattern of expression of the mu opioid receptor (MOP), its binding properties and its G protein coupling remained unchanged across genotypes, it is unlikely that the loss of morphine analgesia in the cnr1KO and cnr2KO mice is the consequence of MOP malfunction or downregulation due to the absence of its heterodimerization with either the CB1 or the CB2 receptors, at least at the level of the spinal cord.”

http://www.ncbi.nlm.nih.gov/pubmed/24365460

Crosstalk between Dopamine D2 receptors and cannabinoid CB1 receptors regulates CNR1 promoter activity via ERK1/2 signaling.

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“Previously, we found that chronic methamphetamine treatment altered CB1 R-dependent cAMP/PKA/DARPP-32/T34/PP2B signaling and decreased levels of CB1 R protein and mRNA in the nucleus accumbens. These findings suggested the existence of signaling interplay between mesolimbic dopamine and CB1 R. In the current study, we further investigate interactions between CB1 R and D2 R signaling. Activation of either CB1 R or D2 R increased ERK1/2 phosphorylation, while co-stimulation of CB1 R and D2 R evoked an additive effect on the phospho-ERK1/2 signal. This effect was mediated through a PTX-sensitive Gαi/o pathway in primary striatal cells. Furthermore, the mRNA level of CB1 R was increased via D2S R by treatment with D2 R agonist quinpirole in D2S R/C6 glioma cells. This effect could be suppressed by co-treatment with the ERK1/2 inhibitor U0126. To test if D2S R could transcriptionally regulate CB1 R, the 5′-untranslated region (5′-UTR) of the CNR1 gene was sequenced from rat brain. Results showed that the CNR1 gene includes two exons, which contain 375 bp. of 5′-UTR and are separated by a 17-kb. intron. A luciferase reporter assay showed that the maximal D2S R-responsive promoter activity is located in the -1 to -222 region of CNR1 promoter. Overall, we demonstrate previously unidentified crosstalk between D2 R and CB1 R via ERK1/2 signaling that enhances the expression of CB1 R by modulating its promoter activity.”

http://www.ncbi.nlm.nih.gov/pubmed/23952963

The Cannabinoid 1 Receptor (CNR1) 1359 G/A Polymorphism Modulates Susceptibility to Ulcerative Colitis and the Phenotype in Crohn’s Disease

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“Anecdotal reports suggest that marijuana- or tetrahydrocannabinol-containing products may be effective in alleviating symptoms in patients with ulcerative colitis (UC) and Crohn’s disease (CD). This is supported by recent studies of our group and others suggesting that pharmacological activation of the cannabinoid 1 (CB1) receptor with selective receptor agonists decreases the inflammatory response in various murine models of colonic inflammation…

Recent evidence suggests a crucial role of the endocannabinoid system, including the cannabinoid 1 receptor (CNR1), in intestinal inflammation. We therefore investigated the influence of the CNR1 1359 G/A (p.Thr453Thr; rs1049353) single nucleotide polymorphism (SNP) on disease susceptibility and phenotype in patients with ulcerative colitis (UC) and Crohn’s disease (CD)…

Conclusion

The CNR1 p.Thr453Thr polymorphism appears to modulate UC susceptibility and the CD phenotype. The endocannabinoid system may influence the manifestation of inflammatory bowel diseases, suggesting endocannabinoids as potential target for future therapies.

…our findings provide further evidence that endocannabinoids modulate intestinal inflammation, suggesting that this system could act as a target for future therapeutic interventions.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829088/

Role of cannabinoid receptors and RAGE in inflammatory bowel disease.

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“The endocannabinoid system is involved in many inflammatory diseases, such as Crohn’s disease (CD) and ulcerative colitis (UC). The distribution and expression of cannabinoid receptors 1 (CNR1) and 2 (CNR2) in combination with inflammatory cytokines and RAGE (receptor of advanced glycation end products), which is also overactive in these diseases, in dependency of the extent of inflammation and alteration of the colon barrier is still unclear and needs to be elucidated…

 

CONCLUSION:

We showed that cannabinoid receptors are expressed differentially in inflammatory bowel disease and that the expression seems to be influenced by the underlying disease and by localized inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/21472688

Revisiting CB1 receptor as drug target in human melanoma.

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“Previous studies have indicated the antitumoral effect of human melanocytes, human melanoma cell lines expressing CB1 receptor (CB1), and of the peritumoral administration of endocannabinoids. In the present study, we systematically screened several human melanoma cell lines for the expression of CNR1 and demonstrated transcription of the authentic gene. The product of CNR1, the CB1 protein, was found localized to the cell membrane as well as to the cytoskeleton. Further, the studied human melanoma cell lines expressed functional CB1 since physiological and synthetic ligands, anandamide (AEA), Met-F-AEA, ACEA and AM251 showed a wide range of biological effects in vitro, for example anti-proliferative, proapoptotic and anti-migratory. More importantly, our studies revealed that systemic administration of a stable CB1 agonist, ACEA, into SCID mice specifically inhibited liver colonization of human melanoma cells.

Since therapeutic options for melanoma patients are still very limited, the endocannabinoid-CB1 receptor system may offer a novel target.”

http://www.ncbi.nlm.nih.gov/pubmed/22447182

Presence of functional cannabinoid receptors in human endocrine pancreas.

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“We examined the presence of functional cannabinoid receptors 1 and 2 (CB1, CB2) in isolated human islets, phenotyped the cells producing cannabinoid receptors and analysed the actions of selective cannabinoid receptor agonists on insulin, glucagon and somatostatin secretion in vitro. We also described the localisation on islet cells of: (1) the endocannabinoid-producing enzymes N-acyl-phosphatidyl ethanolamine-hydrolysing phospholipase D and diacylglycerol lipase; and (2) the endocannabinoid-degrading enzymes fatty acid amidohydrolase and monoacyl glycerol lipase.

RESULTS:

Human islets of Langerhans expressed CB1 and CB2 (also known as CNR1 and CNR2) mRNA and CB1 and CB2 proteins, and also the machinery involved in synthesis and degradation of 2-AG (the most abundant endocannabinoid, levels of which were modulated by glucose). Immunofluorescence revealed that CB1 was densely located in glucagon-secreting alpha cells and less so in insulin-secreting beta cells. CB2 was densely present in somatostatin-secreting delta cells, but absent in alpha and beta cells. In vitro experiments revealed that CB1 stimulation enhanced insulin and glucagon secretion, while CB2 agonism lowered glucose-dependent insulin secretion, showing these cannabinoid receptors to be functional.

CONCLUSIONS/INTERPRETATION:

Together, these results suggest a role for endogenous endocannabinoid signalling in regulation of endocrine secretion in the human pancreas.”

http://www.ncbi.nlm.nih.gov/pubmed/18092149

Predator threat stress promotes long lasting anxiety-like behaviors and modulates synaptophysin and CB1 receptors expression in brain areas associated with PTSD symptoms.

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“Several studies have suggested that changes in hippocampal, prefrontal cortex and amygdaloid complex function are associated with the main symptoms of Posttraumatic Stress Disorder (PTSD). Predator exposure can mimic some aspects of PSTD such as hyperarousal and chronic anxiety…

 The present work evaluated whether the long lasting behavioral effects evoked by predator exposure are associated to long-term changes in the expression of the Cannabinoid receptor 1 (CB1) and the synaptic protein SYP in brain areas…

 Our results suggested that predator exposure causes long-lasting anxiogenic effects associated with hyperactivation of amygdaloid complex and modulation of CB1 receptor in brain areas related to PTSD symptoms.”

http://www.ncbi.nlm.nih.gov/pubmed/23178193

Endocannabinoid system dysfunction in mood and related disorders.

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“The endocannabinoid (EC) system is widely distributed throughout the brain and modulates many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. This article examines the therapeutic potential of cannabinoids in psychiatric disorders.

We propose (hypothesize) that the EC system, which is homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders. Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders. Currently, cannabinoids find a role in pain control. Post mortem and other studies report EC system abnormalities in depression, schizophrenia and suicide. Abnormalities in the cannabinoid-1 receptor (CNR1) gene that codes for cannabinoid-1 (CB1) receptors are reported in psychiatric disorders. However, efficacy trials of cannabinoids in psychiatric disorders are limited but offer some encouragement.

CONCLUSION:

Research is needed to elucidate the role of the EC system in psychiatric disorders and for clinical trials with THC, CBD and synthetic cannabinoids to assess their therapeutic potential.”

http://www.ncbi.nlm.nih.gov/pubmed/21916860