Cannabinoid receptors in brain: pharmacogenetics, neuropharmacology, neurotoxicology, and potential therapeutic applications.
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Tag Archives: CB(1) and CB(2) receptors
Endocannabinoids and cannabinoid receptor genetics.
“This review presents the remarkable advances that have been achieved in marijuana (cannabinoid) research, with the discovery of specific receptors and the existence of naturally occurring cannabis-like substances in the human body and brain.
The last decade has seen more rapid progress in marijuana research than any time in the thousands of years that marijuana has been used by humans, particularly in cannabinoid genomics. The cDNA and genomic sequences encoding G protein-coupled cannabinoid receptors (Cnrs) from several species have now been cloned. Endogenous cannabinoids (endocannabinoids), synthetic and hydrolyzing enzymes and transporters that define neurochemically-specific cannabinoid brain pathways have been identified. Endocannabinoid lipid signaling molecules alter activity at G protein-coupled receptors (GPCR) and possibly at anandamide-gated ion channels, such as vanilloid receptors. Availability of increasingly-specific CB1 and CB2 Cnr antagonists and of CB1 and CB2 Cnr knockout mice have increased our understanding of these cannabinoid systems and provides tantalizing evidence for even more G protein-coupled Cnrs. Initial studies of the Cnr gene structure, regulation and polymorphisms whet our appetite for more information about these interesting genes, their variants and roles in vulnerabilities to addictions and other neuropsychiatric disorders. Behavioral studies of cannabinoids document the complex interactions between rewarding and aversive effects of these drugs.
Pursuing cannabinoid-related molecular, pharmacological and behavioral leads will add greatly to our understanding of endogenous brain neuromodulator systems, abused substances and potential therapeutics. This review of CB1 and CB2 Cnr genes in human and animal brain and their neurobiological effects provide a basis for many of these studies.
Therefore, understanding the physiological cannabinoid control system in the human body and brain will contribute to elucidating this natural regulatory mechanism in health and disease.”
Update on the endocannabinoid system as an anticancer target.
“INTRODUCTION:
Recent studies have shown that the endocannabinoid system (ECS) could offer an attractive antitumor target. Numerous findings suggest the involvement of this system (constituted mainly by cannabinoid receptors, endogenous compounds and the enzymes for their synthesis and degradation) in cancer cell growth in vitro and in vivo.
AREAS COVERED:
This review covers literature from the past decade which highlights the potential of targeting the ECS for cancer treatment. In particular, the levels of endocannabinoids and the expression of their receptors in several types of cancer are discussed, along with the signaling pathways involved in the endocannabinoid antitumor effects. Furthermore, the beneficial and adverse effects of old and novel compounds in clinical use are discussed.
EXPERT OPINION:
One direction that should be pursued in antitumor therapy is to select compounds with reduced psychoactivity. This is known to be connected to the CB1 receptor; thus, targeting the CB2 receptor is a popular objective. CB1 receptors could be maintained as a target to design new compounds, and mixed CB1-CB2 ligands could be effective if they are able to not cross the BBB. Furthermore, targeting the ECS with agents that activate cannabinoid receptors or inhibitors of endogenous degrading systems such as fatty acid amide hydrolase inhibitors may have relevant therapeutic impact on tumor growth. Additional studies into the downstream consequences of endocannabinoid treatment are required and may illuminate other potential therapeutic targets.” http://www.ncbi.nlm.nih.gov/pubmed/21244344
“Update on the endocannabinoid system as an anticancer target” http://www.tandfonline.com/doi/abs/10.1517/14728222.2011.553606?journalCode=iett20
Established and potential therapeutic applications of cannabinoids in oncology.
Abstract
“Cannabis occurs naturally in the dried flowering or fruiting tops of the Cannabis sativa plant. Cannabis is most often consumed by smoking marihuana. Cannabinoids are the active compounds extracted from cannabis. Recently, there has been renewed interest in cannabinoids for medicinal purposes. The two proven indications for the use of the synthetic cannabinoid (dronabinol) are chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Other possible effects that may prove beneficial in the oncology population include analgesia, antitumor effect, mood elevation, muscle relaxation, and relief of insomnia. Two types of cannabinoid receptors, CB1 and CB2, have been detected. CB1 receptors are expressed mainly in the central and peripheral nervous system. CB2 receptors are found in certain nonneuronal tissues, particularly in the immune cells. Recent discovery of both the cannabinoid receptors and endocannabinoids has opened a new era in research on the pharmaceutical applications of cannabinoids. The use of cannabinoids should be continued in the areas indicated, and further studies are needed to evaluate other potential uses in clinical oncology.”
Cannabinoid receptor ligands as potential anticancer agents–high hopes for new therapies?
“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.”
Therapeutic potential of cannabinoid receptor ligands: current status.
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.”
Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation.
“This review covers reports published in the last 5 years on the anti-inflammatory activities of all classes of cannabinoids, including phytocannabinoids such as tetrahydrocannabinol and cannabidiol, synthetic analogs such as ajulemic acid and nabilone, the endogenous cannabinoids anandamide and related compounds, namely, the elmiric acids, and finally, noncannabinoid components of Cannabis that show anti-inflammatory action. It is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation. A possible mechanism for these actions is suggested involving increased production of eicosanoids that promote the resolution of inflammation. This differentiates these cannabinoids from cyclooxygenase-2 inhibitors that suppress the synthesis of eicosanoids that promote the induction of the inflammatory process.”
“INTRODUCTION
This review is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation. Other reviews cover certain aspects of this subject and the reader is referred to them for a discussion of earlier reports. In this review are reports published in the last 5 years on the activities of all classes of cannabinoids, including the endogenous cannabinoids such as anandamide, related compounds such as the elmiric acids (EMAs), and noncannabinoid components of Cannabis that show anti-inflammatory action. An interesting recently published example of the latter one is caryophyllene, an abundant component of Cannabis oil that shows anti-inflammatory activity and has high affinity for cannabinoid receptor 2 (CB2; 5).”
“Phytocannabinoids: Tetrahydrocannabinol and Cannabidiol”
“PLANT PREPARATIONS AND NONCANNABINOID CONSTITUENTS OF CANNABIS”
“Cannabis sativa is a complex botanical, and it is not unlikely that the therapeutic benefits of marijuana are due to some of the more than 60 cannabinoids and 200–250 noncannabinoid constituents of the plant. One noncannabinoid, the geranylated flavone cannflavin A (Fig. 5), is 30 times more potent than aspirin as an inhibitor of prostaglandin E2 . These potentially important findings have been overlooked, as most attention in marijuana research has been directed to the analgesic effects of the plant and to mechanisms of psychoactivity. A further example that this line of inquiry has remained dormant is a series of overlooked observations, which demonstrate potent anti-inflammatory actions of a crude marijuana extract and of the nonpsychoactive Cannabis constituents, CBD, cannabinol, and cannabichromene in the carrageenan paw edema model of acute inflammation in rats. Volatile oil products of the plant also have biological activity. Thus, pyrolysis products may add to the therapeutic properties of smoked marijuana. Several of the most abundant cannabinoid and noncannabinoid constituents of C. sativa are nonpsychoactive.”
“Flavonoids are ubiquitous plant phenolic compounds that consist of two aromatic rings linked by a three carbon bridge. They are attracting interest because of their antioxidant, antitumor, anti-inflammatory, and antimicrobial activities. The flavone luteolin, a constituent of C. sativa, is also found in spices and in vegetables such as celery and green pepper. When added to peripheral blood mononuclear cells in vitro, luteolin suppresses production of the inflammatory cytokines TNFα, IL-1b, and IL-6, actions that relate to a selective reduction in numbers of monocytes. Perhaps more importantly, luteolin inhibits growth of Plasmodium falciparum in vitro and protects against induction of colon cancer in mice.”
“CONCLUSIONS
Possibly the very earliest literature reference on Cannabis describes its use as an anti-inflammatory agent. The Chinese emperor Shen-nung (ca. 2000 B.C.), in a work called Pen-ts’ao Ching, noted many of the effects of Cannabis in humans. Among other properties, it was claimed that cannabis “undoes rheumatism”, suggesting possible anti-inflammatory effects. The reports described in this review of the current literature provide support for the claims made by the ancient Chinese healers. These more recent publications include relief from chronic neuropathic pain, fibromyalgia, rheumatoid arthritis, and postoperative pain. In addition, a large body of preclinical data on all classes of cannabinoids, including the endogenous examples, point to a variety of therapeutic targets for cannabinoids and important roles for the endocannabinoids in the physiology of inflammation.”
Endocannabinoid overactivity and intestinal inflammation
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”
Cannabinoids in intestinal inflammation and cancer.
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.”
Why Cannabis Stems Inflammation
“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