Tag Archives: G-Protein coupled receptors

Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies.

Posted on by
Reply

“The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides (enkephalins, endorphins, and dynorphins).

The endogenous cannabinoid system comprises lipid neuromodulators (endocannabinoids), enzymes for their synthesis and their degradation and two well-characterized receptors, cannabinoid receptors CB1 and CB2.

These systems play a major role in the control of pain as well as in mood regulation, reward processing and the development of addiction.

Both opioid and cannabinoid receptors are coupled to G proteins and are expressed throughout the brain reinforcement circuitry.

A better understanding of opioid-cannabinoid interactions may provide novel strategies for therapies in addicted individuals.”

http://www.ncbi.nlm.nih.gov/pubmed/25698968

The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway.

Posted on by
Reply

“The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain.

In particular, the CB1 receptor is highly expressed in the basal ganglia, mostly on terminals of medium-sized spiny neurons, where it plays a key neuromodulatory function.

The CB1 receptor also confers neuroprotection in various experimental models of striatal damage…

Here, by using an array of pharmacological, genetic and pharmacogenetic approaches, we show that (1) CB1receptor engagement protects striatal cells from excitotoxic death via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin complex 1 pathway, which, in turn, (2) induces brain-derived neurotrophic factor (BDNF) expression through the selective activation of BDNF gene promoter IV, an effect that is mediated by multiple transcription factors.

Collectively, these findings unravel a molecular link between CB1 receptor activation and BDNF expression, and support the relevance of the CB1/BDNF axis in promoting striatal neuron survival.”

http://www.ncbi.nlm.nih.gov/pubmed/25698444

Evaluation of Phytocannabinoids from High Potency Cannabis sativa using In Vitro Bioassays to Determine Structure-Activity Relationships for Cannabinoid Receptor 1 and Cannabinoid Receptor 2.

Posted on by
Reply

“Cannabis has been around for thousands of years and has been used recreationally, medicinally, and for fiber.

Over 500 compounds have been isolated from Cannabis sativa with approximately 105 being cannabinoids. Of those 105 compounds, Δ9-tetrahydrocannabinol has been determined as the primary constituent, which is also responsible for the psychoactivity associated with Cannabis.

Cannabinoid receptors belong to the large superfamily of G protein-coupled receptors.

Targeting the cannabinoid receptors has the potential to treat a variety of conditions such as pain, neurodegeneration, appetite, immune function, anxiety, cancer, and others.

Developing in vitro bioassays to determine binding and functional activity of compounds has the ability to lead researchers to develop a safe and effective drug that may target the cannabinoid receptors…”

http://www.ncbi.nlm.nih.gov/pubmed/25419092

Endocannabinoid-mediated modulation of Gq/11 protein-coupled receptor signaling-induced vasoconstriction and hypertension.

Posted on by
Reply

“Activation of G protein-coupled receptors (GPCRs) can induce vasoconstriction via calcium signal-mediated and Rho-dependent pathways…

Our aim was to provide evidence that GPCR signaling-induced 2-AG production and activation of vascular type1 cannabinoid receptors (CB1R) is capable of reducing agonist-induced vasoconstriction and hypertension…

Pharmacological or genetic loss of CB1R function augmented AngII-induced blood pressure rise in mice.

These data demonstrate that vasoconstrictor effect of GPCR agonists is attenuated via Gq/11-mediated vascular endocannabinoid formation.

Agonist-induced endocannabinoid-mediated CB1R activation is a significant physiological modulator of vascular tone.

Thus, the selective modulation of GPCR signaling-induced endocannabinoid release has a therapeutic potential in case of increased vascular tone and hypertension.”

http://www.ncbi.nlm.nih.gov/pubmed/25595485

http://www.thctotalhealthcare.com/category/hypertension-high-blood-pressure/

Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment

Posted on by
Reply

Figure 1.

“THE CONSEQUENCES OF ISCHEMIC INJURY in liver, heart, and brain can be ameliorated by cannabinoids, a group of diverse compounds that include constituents of the plant Cannabis sativa (phytocannabinoids), endogenous lipids (endocannabinoids), and synthetic substances. Most of the effects of cannabinoids are mediated by the G-protein-coupled receptors cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2)… 

Cannabinoids protect against ischemic stroke…

Activation of the cannabinoid 2 receptor (CB2) reduces ischemic injury in several organs…

In conclusion, our data demonstrate that by activating p38 in neutrophils, CB2 agonists inhibit neutrophil recruitment to the brain and protect against ischemic brain injury.”

http://www.fasebj.org/content/24/3/788.long

Sickle Cell Pain May be Managed with Cannabis

Posted on by
Reply

“Can Medical Cannabis Help to Cure SCD?”

Sickle Cell Disease Pain May Be Managed 2

“Sickle cell disease (SCD) is a hereditary condition caused by a mutation in the haemoglobin gene, which leads to symptoms of anaemia, extreme pain, and organ damage if unmanaged.”

Sickle Cell Disease Pain May Be Managed 1

“Individuals suffering from SCD are far more likely to use cannabis than the general population, potentially for its analgesic properties.

In 2010, researchers at the University of Minnesota found that the synthetic THC analogue CP 55,940 was as effective as morphine sulphate in treating SCD-related severe pain in transgenic mice expressing human sickle haemoglobin, and that it was effective at smaller doses than the opioid.

In 2011, a further paper submitted by the same researchers to Blood (the Journal of the American Association of Hematology) indicated that CP 55,940 ameliorated severe pain associated with the hypoxia/reoxygenation cycle. CP 55,940 is a full agonist of both CB receptors, and is thought to act as an antagonist at the GPR55 receptor.

As well as this, cannabis has been repeatedly shown to act as a vasodilator, which could in itself assist in easing the blockages caused by build-up of sickle cells…

SCD is a painful and debilitating disease, and the overall inefficacy of opioid treatments and resultant poor quality of life for many sufferers is an indication that our approach to it is far from perfect.

If cannabis is a good candidate to replace opioids, it should be implemented forthwith to prevent ongoing suffering for existing patients.”

http://sensiseeds.com/en/blog/sickle-cell-pain-may-managed-cannabis/

Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling.

Posted on by
Reply

“The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. As a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells.

Here, we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo.

These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology.”

http://www.ncbi.nlm.nih.gov/pubmed/24942731

http://www.thctotalhealthcare.com/category/cancer/

Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia

Posted on by
Reply

Figure 1

“Although cannabinoids have been used for millennia for treating pain and other symptoms, their mechanisms of action remain obscure.

With the heralded identification of multiple G-protein-coupled receptors (GPCRs) mediating cannabinoid effects nearly two decades ago, the mystery of cannabinoid pharmacology was thought to be solved…

Despite the wealth of information on cannabinoid-induced peripheral antihyperalgesic and antinociceptive effects in many pain models, the molecular mechanism(s) for these actions remains unknown.

Although metabotropic cannabinoid receptors have important roles in many pharmacological actions of cannabinoids, recent studies have led to the recognition of a family of at least five ionotropic cannabinoid receptors (ICRs). The known ICRs are members of the family of transient receptor potential (TRP) channels and include TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1.

Cannabinoid activation of ICRs can result in desensitization of the TRPA1 and TRPV1 channel activities, inhibition of nociceptors and antihyperalgesia and antinociception in certain pain models.

Thus, cannabinoids activate both metabotropic and ionotropic mechanisms to produce peripheral analgesic effects.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2863326/

Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kappaB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation.

Posted on by
Reply

<br /> FIGURE 1.<br />

“Cannabinoids are compounds derived from the Cannabis sativa (marijuana) plant, as well as produced endogenously in the brain and by immune cells. Cannabinoids mediate their effect through cannabinoid receptors (CB), designated CB1 and CB2, which belong to a superfamily of G-protein-coupled receptors.

CB1 receptors are expressed at high levels in CNS, where they regulate psychoactivity. CB1 receptors are also expressed on immune cells. In contrast, the CB2 receptors are primarily expressed on immune cells and do not contribute to the psychoactivity. The presence of endogenous CB-ligand systems in immune cells suggests that they may play a critical physiological role, the precise nature of which remains to be characterized.

Cannabinoids can decrease the immune response… Cannabinoids have also been widely used in the treatment of pain and inflammation.

Moreover, preliminary studies have shown the possible use of cannabinoids in the treatment of autoimmune diseases such as multiple sclerosis.

Recent studies from our lab demonstrated that Δ9-tetrahydrocannabinol (THC) can trigger apoptosis in vivo in thymocytes and splenocytes, which may account for immunosuppression.

 We demonstrate for the first time that THC and endocannabinoids such as anandamide can induce apoptosis in DCs through activation of CB1 and CB2 receptors.

These studies provide the basis for understanding the mechanism by which THC triggers immunosuppression and mediates anti-inflammatory properties.

Many studies have suggested the use of THC or related cannabinoids in the treatment of autoimmune diseases.”

http://www.jimmunol.org/content/173/4/2373.long

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

Posted on by
Reply

“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