Phytocannabinoids and endocannabinoids.
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Monthly Archives: October 2012
[The mechanism of action of cannabis and cannabinoids].
Abstract
“The effect of cannabis can be explained on the basis of the function of the cannabinoid receptor system, which consists of CB receptors (CB1, CB2), endoligands to activate these receptors and an enzyme–fatty acid amidohydrolase–to metabolize the endoligands. The endoligands of the cannabinoid receptor system are arachidonic acid-like substances, and are called endocannabinoids. Indications exist that the body also contains arachidonic acid-like substances that inhibit fatty acid amido hydrolase. Various cannabinoids have diverse effects on the receptors, functioning as agonists, antagonists or partial antagonists, as well as affecting the vanilloid receptor. Many known effects of cannabis can be explained on the basis of this mechanism of action as can the use of cannabis in various conditions including multiple sclerosis, Parkinson’s disease, glaucoma, nausea, vomiting and rheumatoid arthritis.”
Cannabis and cannabinoids: pharmacology and rationale for clinical use.
Abstract
“It is now known that there are at least two types of cannabinoid receptors. These are CB1 receptors, present mainly on central and peripheral neurones, and CB2 receptors, present mainly on immune cells. Endogenous cannabinoid receptor agonists (‘endocannabinoids’) have also been identified. The discovery of this ‘endogenous cannabinoid system’ has led to the development of selective CB1 and CB2 receptor ligands and fueled renewed interest in the clinical potential of cannabinoids. Two cannabinoid CB1 receptor agonists are already used clinically, as antiemetics or as appetite stimulants. These are D 9 – tetrahydrocannabinol (THC) and nabilone. Other possible uses for CB1 receptor agonists include the suppression of muscle spasm/spasticity associated with multiple sclerosis or spinal cord injury, the relief of chronic pain and the management of glaucoma and bronchial asthma. CB1 receptor antagonists may also have clinical applications, e. g. as appetite suppressants and in the management of schizophrenia or disorders of cognition and memory. So too may CB2 receptor ligands and drugs that activate cannabinoid receptors indirectly by augmenting endocannabinoid levels at cannabinoid receptors. When taken orally, THC seems to undergo variable absorption and to have a narrow ‘therapeutic window’ (dose range in which it is effective without producing significant unwanted effects). This makes it difficult to predict an oral dose that will be both effective and tolerable to a patient and indicates a need for better cannabinoid formulations and modes of administration. For the therapeutic potential of cannabis or CB1 receptor agonists to be fully exploited, it will be important to establish objectively and conclusively (a) whether these agents have efficacy against selected symptoms that is of clinical significance and, if so, whether the benefits outweigh the risks, (b) whether cannabis has therapeutic advantages over individual cannabinoids, (c) whether there is a need for additional drug treatments to manage any of the disorders against which cannabinoids are effective, and (d) whether it will be possible to develop drugs that have reduced psychotropic activity and yet retain the ability to act through CB1 receptors to produce their sought-after effects.”
Cannabinoids in health and disease
Abstract
“Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson’s disease, Huntington’s disease, Tourette’s syndrome, Alzheimer’s disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable – instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and – in cases where it is impossible to separate the desired clinical action and the psychoactivity – just to monitor these side effects carefully.”
Cancer
“The antiproliferative action of cannabinoids on cancer cells was first noticed in the 1970s. Since then cannabinoids were found to act on various cancer cell lines, through various mechanisms. Cannabinoids were also found to be suppressors of angiogenesis and tumor invasion. Our knowledge on the anticancer activity of cannabinoids is rapidly expanding.”
Conclusion
“Many drugs used today can cause addiction and are misused and abused, for example opiates, cocaine, benzodiazepines, barbiturates, cholinergic agonists, ketamine, dopaminergic agonists, amphetamines, and others. Nevertheless they are still an important part of our pharmacopeia. Marijuana was used for centuries as a medicinal plant, but during the last century, because of its abuse and addictive potential it was taken out of clinical practice. Now, we believe that its constituents and related compounds should be brought back to clinical use. The reasons are: (i) the therapeutic potential of CB1 agonists is huge, as described in this review; (ii) for local action, topical CB1 agonists, or agonists that do not penetrate the blood-brain barrier, can be used; (iii) cannabinoids acting specifically on CB2 receptors, which cause no psychoactivity, may be used on peripheral targets (such as osteoporosis, which is only one of many examples); (iv) there are additional, new cannabinoid targets distinct from the CB1/CB2 receptors which do not cause psychoactivity; (v) there are cannabinoids, such as CBD, which do not cause psychoactivity, but have various therapeutic effects.”
A novel nonpsychotropic cannabinoid, HU-211, in the treatment of experimental pneumococcal meningitis.
Abstract
“Typical features of pneumococcal meningitis have been demonstrated in rats inoculated with Streptococcus pneumoniae. HU-211, a novel noncompetitive N-methyl-D-aspartate antagonist recently demonstrated to inhibit tumor necrosis factor-alpha production under various conditions, improves recovery in some experimental models of brain injury. The present study tested the efficacy of HU-211 in combination with antimicrobial therapy in reducing brain damage in experimental pneumococcal meningitis. S. pneumoniae-infected rats were treated with saline alone, ceftriaxone alone, or with combination of ceftriaxone and HU-211 18 h after inoculation of the bacteria. Brain edema and blood-brain barrier impairment 48 h after infection were significantly (P<.05) reduced suggest that HU-211 when given concomitantly with antibiotics attenuates brain damage in the rat model of pneumococcal meningitis.”
Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis.
“Pneumococcal meningitis is a life-threatening disease characterized by an acute infection affecting the pia matter, arachnoid and subarachnoid space. The intense inflammatory response is associated with a significant mortality rate and neurologic sequelae, such as, seizures, sensory-motor deficits and impairment of learning and memory.
The aim of this study was to evaluate the effects of acute and extended administration of cannabidiol on pro-inflammatory cytokines and behavioral parameters in adult Wistar rats submitted to pneumococcal meningitis.
The extended administration of cannabidiol at different doses reduced the TNF-α level in frontal cortex. Prolonged treatment with canabidiol, 10mg/kg, prevented memory impairment in rats with pneumococcal meningitis.
Although descriptive, our results demonstrate that cannabidiol has anti-inflammatory effects in pneumococcal meningitis and prevents cognitive sequel.” https://www.ncbi.nlm.nih.gov/pubmed/23085269
“Although descriptive, our results demonstrate that chronic treatment with CBD plays an anti-inflammatory role in pneumococcal meningitis. Furthermore, it prevents cognitive damage, possibly representing a new pharmacological approach towards pneumococcal meningitis.” https://www.sciencedirect.com/science/article/pii/S0014299912008485?via%3Dihub
Pharmacology of cannabinoid CB1 CB2 receptors.
Abstract
“There are at least two types of cannabinoid receptors, CB1 and CB2, both coupled to G-proteins. CB1 receptors are present in the central nervous system and CB1 and CB2 receptors in certain peripheral tissues. The existence of endogenous cannabinoid receptor agonists has also been demonstrated. These discoveries have led to the development of selective cannabinoid CB1 and CB2 receptor ligands. This review focuses on the classification, binding properties, effector systems and distribution of cannabinoid receptors. It also describes the various cannabinoid receptor agonists and antagonists now available and considers the main in vivo and in vitro bioassay methods that are generally used.”
Pharmacology of cannabinoid receptor ligands.
Abstract
“Mammalian tissues contain at least two types of cannabinoid receptor, CB1 and CB2, both coupled to G proteins. CB1 receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB2 receptors occur in certain non-neuronal tissues, particularly in immune cells. The existence of endogenous ligands for cannabinoid receptors has also been demonstrated. The discovery of this endogenous cannabinoid system has been paralleled by a renewed interest in possible therapeutic applications of cannabinoids, for example in the management of pain and in the suppression of muscle spasticity/spasm associated with multiple sclerosis or spinal cord injury. It has also prompted the development of a range of novel cannabinoid receptor ligands, including several that show marked selectivity for CB1 or CB2 receptors. This review summarizes current knowledge about the in vitro pharmacological properties of important CB1 and CB2 receptor ligands. Particular attention is paid to the binding properties of these ligands, to the efficacies of cannabinoid receptor agonists, as determined using cyclic AMP or [35S]GTPgammaS binding assays, and to selected examples of how these pharmacological properties can be influenced by chemical structure. The in vitro pharmacological properties of ligands that can potently and selectively oppose the actions of CB1 or CB2 receptor agonists are also described. When administered by themselves, some of these ligands produce effects in certain tissue preparations that are opposite in direction to those produced by cannabinoid receptor agonists and the possibility that the ligands producing such inverse cannabimimetic effects are inverse agonists rather than pure antagonists is discussed.”
Ligands that target cannabinoid receptors in the brain: from THC to anandamide and beyond.
Abstract
“A major finding–that (-)-trans-Delta(9)-tetrahydrocannabinol (Delta(9)-THC) is largely responsible for the psychotropic effects of cannabis–prompted research in the 1970s and 1980s that led to the discovery that this plant cannabinoid acts through at least two types of cannabinoid receptor, CB(1) and CB(2), and that Delta(9)-THC and other compounds that target either or both of these receptors as agonists or antagonists have important therapeutic applications. It also led to the discovery that mammalian tissues can themselves synthesize and release agonists for cannabinoid receptors, the first of these to be discovered being arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol. These ‘endocannabinoids’ are released onto their receptors in a manner that appears to maintain homeostasis within the central nervous system and sometimes either to oppose or to mediate or exacerbate the unwanted effects of certain disorders. This review provides an overview of the pharmacology of cannabinoid receptors and their ligands. It also describes actual and potential clinical uses both for cannabinoid receptor agonists and antagonists and for compounds that affect the activation of cannabinoid receptors less directly, for example by inhibiting the enzymatic hydrolysis of endocannabinoids following their release.”
The pharmacology of cannabinoid receptors and their ligands: an overview.
Abstract
“Mammalian tissues express at least two cannabinoid receptor types, CB1 and CB2, both G protein coupled. CB1 receptors are found predominantly at nerve terminals where they mediate inhibition of transmitter release. CB2 receptors occur mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous agonists for cannabinoid receptors also exist, and are all eicosanoids. The first-discovered of these ‘endocannabinoids’ was arachidonoylethanolamide and there is convincing evidence that this ligand and some of its metabolites can activate vanilloid VRI (TRPV1) receptors. Certain cannabinoids also appear to have TRPV1-like and/or non-CB1, non-CB2, non-TRPV1 targets. Several CB1- and CB2-selective agonists and antagonists have been developed. Antagonists include the CB1-selective SR141716A, AM251, AM281 and LY320135, and the CB2-selective SR144528 and AM630. These all behave as inverse agonists, one indication that CB1 and CB2 receptors can exist in a constitutively active state. ‘Neutral’ cannabinoid receptor antagonists have also been developed. CB1 and/or CB2 receptor activation appears to ameliorate inflammatory and neuropathic pain and certain multiple sclerosis symptoms. This might be exploited clinically by using CB1, CB2 or CB1/CB2 agonists, or inhibitors of the membrane transport or catabolism of endocannabinoids that are released in increased amounts, at least in animal models of pain and multiple sclerosis. We have recently discovered the presence of an allosteric site on the CB1 receptor. Consequently, it may also prove possible to enhance ‘autoprotective’ effects of released endocannabinoids with CB1 allosteric enhancers or, indeed, to reduce proposed ‘autoimpairing’ effects of released endocannabinoids such as excessive food intake with CB1 allosteric antagonists.”