Tag Archives: cannabinoid receptors

Cannabinoid receptor ligands as potential anticancer agents–high hopes for new therapies?

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“OBJECTIVES:

The endocannabinoid system is an endogenous lipid signalling network comprising arachidonic-acid-derived ligands, cannabinoid (CB) receptors, transporters and endocannabinoid degrading enzymes. The CB(1) receptor is predominantly expressed in neurons but is also co-expressed with the CB(2) receptor in peripheral tissues. In recent years, CB receptor ligands, including Delta(9)-tetrahydrocannabinol, have been proposed as potential anticancer agents.

KEY FINDINGS:

This review critically discusses the pharmacology of CB receptor activation as a novel therapeutic anticancer strategy in terms of ligand selectivity, tissue specificity and potency. Intriguingly, antitumour effects mediated by cannabinoids are not confined to inhibition of cancer cell proliferation; cannabinoids also reduce angiogenesis, cell migration and metastasis, inhibit carcinogenesis and attenuate inflammatory processes. In the last decade several new selective CB(1) and CB(2) receptor agents have been described, but most studies in the area of cancer research have used non-selective CB ligands. Moreover, many of these ligands exert prominent CB receptor-independent pharmacological effects, such as activation of the G-protein-coupled receptor GPR55, peroxisome proliferator-activated receptor gamma and the transient receptor potential vanilloid channels.

SUMMARY:

The role of the endocannabinoid system in tumourigenesis is still poorly understood and the molecular mechanisms of cannabinoid anticancer action need to be elucidated. The development of CB(2)-selective anticancer agents could be advantageous in light of the unwanted central effects exerted by CB(1) receptor ligands. Probably the most interesting question is whether cannabinoids could be useful in chemoprevention or in combination with established chemotherapeutic agents.”

http://www.ncbi.nlm.nih.gov/pubmed/19589225

Therapeutic potential of cannabinoid receptor ligands: current status.

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Abstract

“There are at least two types of cannabinoid receptors, CB1 also named CNR1 and CB2 also named CNR2, both coupled to G proteins. CB1 receptors exist primarily on central and peripheral neurons. CB2 receptors are present mainly on immune cells. Endogenous agonists for cannabinoid receptors (endocannabinoids) have also been discovered, the most important being arachidonoyl ethanolamide (anandamide), 2-arachidonoyl glycerol (2-AG), and 2-archidonyl glyceryl ether. Following their release, endocannabinoids are removed from the extracellular space and then degraded by intracellular enzymic hydrolysis. CB1/CB2 agonists are already used clinically as antiemetic or to stimulate appetite. Potential therapeutic uses of cannabinoid receptor agonists include the management of multiple sclerosis, spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, vasodilatation that accompanies advanced cirrhosis, and cancer.”

http://www.ncbi.nlm.nih.gov/pubmed/16810344

Endocannabinoid overactivity and intestinal inflammation

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Abstract

“Cannabinoid receptors of type 1 and 2 (CB1 and CB2), endogenous ligands that activate them (endocannabinoids), and mechanisms for endocannabinoid biosynthesis and inactivation have been identified in the gastrointestinal system. Activation of CB1 receptors by endocannabinoids produces relaxation of the lower oesophageal sphincter and inhibition of gastric acid secretion, intestinal motility, and fluid stimulated secretion. However, stimulation of cannabinoid receptors impacts on gastrointestinal functions in several other ways. Recent data indicate that the endocannabinoid system in the small intestine and colon becomes over stimulated during inflammation in both animal models and human inflammatory disorders. The pathological significance of this “endocannabinoid overactivity” and its possible exploitation for therapeutic purposes are discussed here.”

 

“The endocannabinoid system of the gastrointestinal tract includes not only cannabinoid receptors but also endogenous agonists of these receptors, as well as mechanisms for their biosynthesis and inactivation”

 

“The main psychotropic constituent of the plant Cannabis sativa and marijuana, Δ9‐tetrahydrocannabinol, exerts its pharmacological effects by activating two G protein coupled cannabinoid receptors.1These are the CB1 receptor, present in central and peripheral nerves (including the human enteric nervous system), and the CB2 receptor, expressed abundantly in immune cells. In rodents, CB1 receptor immunoreactivity has been detected in discrete nuclei of the dorsovagal complex (involved in emesis), and in efferents from the vagal ganglia and in enteric (myenteric and submucosal) nerve terminals where they inhibit excitatory (mainly cholinergic) neurotransmission. In vivo pharmacological studies have shown that activation of CB1 receptors reduces emesis, produces inhibition of gastric acid secretion8 and relaxation of the lower oesophageal sphincter (two effects that might be beneficial in the treatment of gastro‐oesophageal reflux disease), and inhibits intestinal motility and secretion. Consistent with immunohistochemical data showing that CB2 receptors are particularly evident in colonic tissues from patients with inflammatory bowel diseases (IBD), evidence suggests that CB2 inhibits intestinal motility during certain pathological states.1″

 

“…endocannabinoids convey protection from enteric hypersecretory states (for example, cholera toxin induced diarrhoea), which is in agreement with anecdotal reports from folk medicine on the use of Cannabis sativa in the treatment of diarrhoea.“

 

“Overactivity of the endocannabinoid system is becoming a well established concept in human intestinal conditions with an inflammatory component”

   

“The inhibitory effects of cannabinoids on intestinal inflammation, as well as on intestinal motility and secretory diarrhoea, observed in preclinical studies, increase the potential for their use in the treatment of IBD”

  

“There is great potential for the development of new therapeutic agents against intestinal inflammation from the endocannabinoid system”

 

“Conclusions: new therapies for the treatment of IBD from the endocannabinoid system”

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1856409/

Targeting the endocannabinoid system: to enhance or reduce?

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Abstract

“As our understanding of the endocannabinoids improves, so does the awareness of their complexity. During pathological states, the levels of these mediators in tissues change, and their effects vary from those of protective endogenous compounds to those of dysregulated signals. These observations led to the discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases. When moving to the clinic, however, the pleiotropic nature of endocannabinoid functions will require careful judgement in the choice of patients and stage of the disorder for treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/18446159

Cannabinoids in intestinal inflammation and cancer.

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Abstract

“Emerging evidence suggests that cannabinoids may exert beneficial effects in intestinal inflammation and cancer. Adaptive changes of the endocannabinoid system have been observed in intestinal biopsies from patients with inflammatory bowel disease and colon cancer. Studies on epithelial cells have shown that cannabinoids exert antiproliferative, antimetastatic and apoptotic effects as well as reducing cytokine release and promoting wound healing. In vivo, cannabinoids – via direct or indirect activation of CB(1) and/or CB(2) receptors – exert protective effects in well-established models of intestinal inflammation and colon cancer. Pharmacological elevation of endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer.”

http://www.ncbi.nlm.nih.gov/pubmed/19442536

Pot Chemical May Curb Inflammation – WebMD

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“Marijuana’s active ingredient may curb inflammation and help treat skin allergies.

That news comes from researchers including Meliha Karsak, PhD, and Thomas Tuting, MD, of Germany’s University of Bonn.

Marijuana’s key compound, THC, is a type of chemical called a cannabinoid. The brain contains two types of cannabinoid receptors.

Karsak and colleagues studied mice born with or without cannabinoid receptors. The mice wore ear tags to identify them; those ear tags contained nickel.

The mice without cannabinoid receptors were particularly likely to have allergic skin reactions to the nickel in the ear tags.

The scientists reasoned that the mice’s allergies may have been linked to their lack of cannabinoid receptors.

Karsak’s team tested that theory in several experiments.

First, they turned off cannabinoid receptors in healthy mice. Those mice then became more likely to develop skin inflammation near their nickel ear tags.

Next, the researchers exposed other mice with cannabinoid receptors to a skin irritant. Some of the mice got THC shots after being exposed to the irritant. Others got a THC skin lotion before and after exposure to the irritant.

The THC shot and lotion both helped soothe the mice’s inflamed skin.

“If we dabbed THC solution onto the animals’ skin shortly before and after applying the allergen, a lot less swelling occurred than normal,” Tuting says in a University of Bonn news release.

In the journal Science, the researchers write that their study “strongly suggests” that the body’s cannabinoid system can help tame inflammation and that THC skin lotions have “promising potential” for treating skin allergies caused by contact with irritating chemicals.

However, the researchers didn’t test the THC lotion on skin allergies in people.”

http://www.webmd.com/allergies/news/20070607/pot-chemical-may-curb-inflammation

“Attenuation of allergic contact dermatitis through the endocannabinoid system…These results demonstrate a protective role of the endocannabinoid system in contact allergy in the skin and suggest a target for therapeutic intervention.”  http://www.ncbi.nlm.nih.gov/pubmed/17556587

Why Cannabis Stems Inflammation

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“Cannabis has long been accredited with anti-inflammatory properties. ETH Zurich researchers, however, have now discovered that it is not only the familiar psychoactive substances that are responsible for this; a compound we take in every day in vegetable nutriment also plays a significant role.

People not only rate cannabis sativa L. highly because of its intoxicating effects; it has also long been used as a medicinal plant. Although the plant has been scrutinized for years, surprising new aspects keep cropping up. For example, researchers from ETH Zurich and Bonn University examined a component in the plant’s essential oil that until then had largely been ignored and found it to have remarkable phar- macological effects. The findings open up interesting perspectives, especially for the prevention and treatment of inflammations.

The hemp plant contains over 450 different substances, only three of which are responsible for its intoxicating effect. They activate the two receptors in the body CB1 and CB2. Whilst the CB1 receptor in the central nervous system influences perception, the CB2 receptor in the tissue plays a crucial role in inhibiting inflammation. If the receptor is activated, the cell releases fewer pro-inflammatory signal substances, or cytokines. The scientists have now discovered that the substance beta-carophyllene, which composes between 12 and 35 percent of the cannabis plant’s essential oil, activates the CB2 receptor selectively.”

http://www.sciencedaily.com/releases/2008/07/080720222549.htm

The role of cannabinoid system on immune modulation: therapeutic implications on CNS inflammation.

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Abstract

“There is a growing amount of evidence suggesting that cannabinoids may be neuroprotective in CNS inflammatory conditions. Advances in the understanding of the physiology and pharmacology of the cannabinoid system have increased the interest of cannabinoids as potential therapeutic targets. Cannabinoid receptors and their endogenous ligands, the endocannabinoids, have been detected in cells of the immune system, as well as in brain glial cells. In the present review it is summarized the effects of cannabinoids on immune reactivity and on the regulation of neuroinflammatory processes associated with brain disorders with special attention to chronic inflammatory demyelinating diseases such as multiple sclerosis.”

http://www.ncbi.nlm.nih.gov/pubmed/16026313

Cannabinoids and the immune system: potential for the treatment of inflammatory diseases?

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Abstract

“Since the discovery of the cannabinoid receptors and their endogenous ligands, significant advances have been made in studying the physiological function of the endocannabinoid system. The presence of cannabinoid receptors on cells of the immune system and anecdotal and historical evidence suggesting that cannabis use has potent immuno-modulatory effects, has led to research directed at understanding the function and role of these receptors within the context of immunological cellular function. Studies from chronic cannabis smokers have provided much of the evidence for immunomodulatory effects of cannabis in humans, and animal and in vitro studies of immune cells such as T cells and macrophages have also provided important evidence. Cannabinoids can modulate both the function and secretion of cytokines from immune cells. Therefore, cannabinoids may be considered for treatment of inflammatory disease. This review article will highlight recent research on cannabinoids and how they interact with the immune system and also their potential use as therapeutic agents for a number of inflammatory disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/16023222

The cannabinoid system and immune modulation

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Figure 1.

“Studies on the effects of marijuana smoking have evolved into the discovery and description of the endocannabinoid system. To date, this system is composed of two receptors, CB1 and CB2, and endogenous ligands including anandamide, 2-arachidonoyl glycerol, and others. CB1 receptors and ligands are found in the brain as well as immune and other peripheral tissues. Conversely, CB2 receptors and ligands are found primarily in the periphery, especially in immune cells. Cannabinoid receptors are G protein-coupled receptors, and they have been linked to signaling pathways and gene activities in common with this receptor family. In addition, cannabinoids have been shown to modulate a variety of immune cell functions in humans and animals and more recently, have been shown to modulate T helper cell development, chemotaxis, and tumor development. Many of these drug effects occur through cannabinoid receptor signaling mechanisms and the modulation of cytokines and other gene products.

It appears the immunocannabinoid system is involved in regulating the brain-immune axis and might be exploited in future therapies for chronic diseases and immune deficiency.”

“The medicinal uses of marijuana were described centuries ago for diseases such as asthma, migraine, pain, convulsions, and anxiety (reviewed in ref.). More recently, emphasis has been placed on marijuana’s putative, beneficial effects on appetite, glaucoma, spasticity in multiple sclerosis, pain, and inflammation.

Recent experimental evidence supports marijuana’s therapeutic potential in some of these maladies.

The active plant ingredients in marijuana belong to the C21-cannabinoid compounds including the primary psychoactive compound, Δ9-tetrahydrocannabinol (THC). This cannabinoid along with others such as Δ8-THC, cannabidiol, and cannabinol, as well as chemical analogs, have been extensively studied over the years for their biological and therapeutic properties. Some of the properties of these agents have included effects on immunity ranging from suppression of resistance to infection to enhancement of IL-1 production by macrophages. These early studies about the immunomodulating effects of these drugs have been the subject of previous overviews and will not be reviewed here. Instead, we will briefly summarize the general features of the cannabinoid system and review recent findings on the structure and function of the cannabinoid system components in the immune system. For convenience, we will refer to this as the “immunocannabinoid” system.

CANNABINOID SYSTEM

Marijuana cannabinoids, analogs, and endocannabinoids”

https://jlb.onlinelibrary.wiley.com/doi/full/10.1189/jlb.0303101?sid=nlm%3Apubmed