The CB1 receptor is abundant in the brain and is also present in other tissues and organs of .. Therefore, the regulatory function of cannabinoids on the tumor . Postepy Hig Med Dosw (Online). ; [The role of the endocannabinoid system in the regulation of endocrine function and in the control of energy. Within the past 15 years, the endocannabinoid system (ECS) has energy balance, as it exerts a regulatory control on every aspect related to the search, .. ECS in other peripheral organs and circulating endocannabinoids.
other functions The ECS and regulatory
The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamide secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall.
For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low. Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the autonomic nervous system. Research found that the CB 1 receptor is expressed presynaptically by motor neurons that innervate visceral organs.
Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from sympathetic nervous system nerves. Other studies have found similar effects in endocannabinoid regulation of intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems. At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in the dorsal horn, possibly by modulating descending noradrenaline input from the brainstem.
The endocannabinoid most researched in pain is palmitoylethanolamide. Palmitoylethanolamide is a fatty amine related to anandamide, but saturated and although initially it was thought that palmitoylethanolamide would bind to the CB1 and the CB2 receptor, later it was found that the most important receptors are the PPAR-alpha receptor , the TRPV receptor and the GPR55 receptor.
Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications  and found to be safe and effective. Basically these data are proof of concept for endocannabinoids and related fatty amines to be therapeutically useful analgesics; palmitoylethanolamide is available under the brand names Normast and PeaPure as nutraceuticals.
Endocannabinoids are involved in placebo induced analgesia responses. Increased endocannabinoid signaling within the central nervous system promotes sleep-inducing effects.
Intercerebroventricular administration of anandamide in rats has been shown to decrease wakefulness and increase slow-wave sleep and REM sleep. Anandamide is an endogenous cannabinoid neurotransmitter that binds to cannabinoid receptors. In mice it was demonstrated that certain features of a runner's high depend on cannabinoid receptors.
Pharmacological or genetic disruption of cannabinoid signaling via cannabinoid receptors prevents the analgesic and anxiety-reducing effects of running. Neuroscientists often utilize transgenic CB 1 knockout mice to discern novel roles for the endocannabinoid system.
While CB 1 knockout mice are healthy and live into adulthood, there are significant differences between CB 1 knockout and wild-type mice. When subjected to a high-fat diet, CB 1 knockout mice tend to be about sixty percent leaner and slightly less hungry than wildtype.
The endocannabinoid system is by molecular phylogenetic distribution of apparently ancient lipids in the plant kingdom, indicative of biosynthetic plasticity and potential physiological roles of endocannabinoid-like lipids in plants,  and detection of arachidonic acid AA indicates chemotaxonomic connections between monophyletic groups with common ancestor dates to around million years ago silurian ; devonian.
From Wikipedia, the free encyclopedia. This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Further information on receptor localization: This section provides insufficient context for those unfamiliar with the subject. Please help improve the article with a good introductory style.
January Learn how and when to remove this template message. The Journal of Sexual Medicine. European Journal of Pharmacology. The traditional view that PA engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system ECS , composed of endogenous lipids, their target receptors, and metabolic enzymes.
Indeed, direct and indirect evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. To our knowledge, the first experimental study aimed at investigating the influence of PA on ECS in humans was carried out in by Sparling and coworkers , who showed increased plasma AEA content after 45 min of moderate intensity exercise on a treadmill or cycle ergometer.
Since then, other human studies have shown increased blood concentrations of AEA A dependence of the increase of AEA concentration on exercise intensity has also been documented.
Several experimental data support the hypothesis that ECS might, at least in part, explain PA effects on brain functions, because: Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's high', which may function to encourage habitual aerobic exercise.
Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes. How mobility and movement are at the center of human evolution. Issues, News, and Reviews Cell Death and Differentiation. British Journal of Pharmacology. Int J Obes Lond. Indeed, a fold increase in the potency of hypocretin-1 to activate the ERK signaling was observed when CB1 and HcrtR1 were co-expressed These data provide unambiguous identification of CB1-HcrtR1 heteromerization, which has a substantial functional impact.
The existence of a cross-talk between the hypocretinergic and endocannabinoid systems is strongly supported by their partially overlapping anatomical distribution and common role in several physiological and pathological processes. However, little is known about the mechanisms underlying this interaction. CB1 is present in neurons of the enteric nervous system and in sensory terminals of vagal and spinal neurons in the gastrointestinal tract Massa et al.
Activation of CB1 is shown to modulate nutrient processing, such as gastric secretion, gastric emptying, and intestinal motility. CB1 is shown to co-localize with the food intake inhibiting neuropeptide, corticotrophin-releasing hormone, in the paraventricular nucleus of the hypothalamus, and with the two orexigenic peptides, melanin-concentrating hormone in the lateral hypothalamus and with pre-pro-orexin in the ventromedial hypothalamus Inui, ; Horvath, The ECS works through many anorexigenic and orexigenic pathways where ghrelin, leptin, adiponectin, endogenous opioids, and corticotropin-releasing hormones are involved Viveros et al.
OX1—CB1 dimerization was suggested to strongly potentiate orexin receptor signaling, but a likely explanation for the signal potentiation is, instead, offered by the ability of OX1 receptor signaling to produce 2-arachidonoyl glycerol, a CB1 receptor ligand, and a subsequent co-signaling of the receptors Haj-Dahmane and Shen, ; Turunen et al.
However, this does not preclude dimerization. Orexin receptor subtypes readily formed homo- and hetero di mers, as suggested by significant BRET signals.
CB1 receptors formed homodimers, and they also heterodimerized with both orexin receptors. However, it is unclear whether this affects their signaling. As orexin receptors efficiently signal via endocannabinoid production to CB1 receptors, dimerization could be an effective way of forming signal complexes with optimal cannabinoid concentrations available for cannabinoid receptors.
Activation of central CB1R The Open Pain Journal. From Bench to Bedside 1st ed. A popular belief has been that endogenous endorphins mediate these beneficial effects. Using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, we demonstrate that cannabinoid receptors mediate acute anxiolysis and analgesia after running.
We thus demonstrate that the endocannabinoid system is crucial for two main aspects of a runner's high. Sedation, in contrast, was not influenced by cannabinoid or opioid receptor blockage, and euphoria cannot be studied in mouse models. An update to the review in Annals of Botany". Recreational and medical applications rights Industrial applications. Autoflowering cannabis Cannabis indica ruderalis sativa Difference between C. Medical cannabis History Timeline Religious and spiritual use Chalice.
Cannabis in pregnancy Dependence Effects of cannabis Long-term Endocannabinoid system Impaired driving. Adult lifetime use by country Annual use by country. Return to class B Uruguay: Decriminalization of non-medical use Rescheduling per the Controlled Substances Act.
Cannabis political parties List of British politicians who have acknowledged cannabis use List of American politicians who have acknowledged cannabis use. ADPF Gonzales v. They are grouped into three main classes: Recent studies provide lines of evidence that cannabinoids, in addition to well-known pharmacological activities as an antiemetic and in the treatment of glaucoma, exhibit anticancer and antiangiogenic properties.
Phytocannabinoids are well-known natural products that are extracted and isolated from the Cannabis sativa L. Marijuana has long been known for its medicinal and recreational properties.
In , Raphael Mechoulam and coworkers isolated one of the most active compounds from Cannabis sativa L. Since then, 60 unique phytocannabinoids, such as cannabidiol CBD , cannabinol CBN , and cannibigerol CBG , together with endogenous cannabinoids, such as anan-damide arachidonoylethanolamine or AEA [ 8 ], and 2-Arachido-noylglycerol 2-AG [ 9 ], have been identified by the Mechoulam research group.
These seminal studies provided the first complete characterization of the endocannabinoid system ECS. Phytocannabinoids are physiologically produced in plant cell substructures called trichomes in the form of resin.
From a biochemical point of view, all subclasses of phytocannabinoids originate from cannabigerol-type CBG molecules, according to the diverse cyclization products of this precursor Fig. Two possible numberings of the C21 phytocannabinoids have been proposed, depending on either the dibenzopyran or monoterpenoid scaffold.
In the present work, we refer to dibenzopyran numbering Fig. Some progenitors of the main subclasses of pytocannabinoids derived from condensation of olivetolic acid and geranyl pyrophosphate are illustrated in Fig. Other classes of pythocannabinoids are derived from the condensation of geranyl pyrophosphate GPP with divarinolic acid instead of olivetolic acid.
In the structure of the latter, propyl side chains replace the pentyl hydrocarbon residue. Four stereoisomers of THC are possible, but only the levorotatory ones occur in nature Table 1. Accordingly, naturally occurring stereoisomers are energetically favored, due to the trans configuration being less strained than the cis configuration.
In , Mechoulam et al. Cannabinol is a weak psychoactive cannabinoid isolated from Cannabis sativa L. It is structurally related to THC, from which it is obtained biosynthetically by oxidation.
Cannabidiol is one of the most abundant phytocannabinoids isolated from Cannabis sativa L. Cannabidiol is poorly soluble in water but has good solubility in polar organic solvents. In the presence of a strong base and oxygen, it is oxidized to quinone [ 20 ]. It can be converted into THC by acid catalyzed cyclization [ 21 ]. The synthesis of CBD has been accomplished by several research groups [ 13 , 22 , 23 ]. For this reason, CBD has aroused increased research interest in its pharmacological properties.
Several studies show CBD to have anti-inflammatory, anticonvulsant, antioxidant, antiemetic, anxiolytic, and antipsychotic properties; thus, it may serve as potential drug for the treatment of neuro-inflammation, epilepsy, oxidative injury, vomiting and nausea, and anxiety and schizophrenia, respectively [ 19 ]. CBD is commercialized in a 1: The drug is currently in phases II and III of clinical trials for Dravet syndrome, common epilepsy, schizophrenia, and other rare syndromes.
Recently, new evidence of other therapeutic activities of CBD has been found in the treatment of cancer and neurodegenerative disorders [ 24 , 25 ]. Endogenous cannabinoids, or endocannabinoids, are capable of binding to CB receptors; they are lipid-like structures corresponding to those depicted in Fig. Endocannabinoids are obtained from arachidonic acid, a common precursor in the biosynthesis of prostaglandins, which are key regulators of inflammatory processes.
These compounds are derived from the non-oxidative metabolism of arachidonic acid by formal condensation with ethanolamine or glycerol, starting from the precursors eicosanoic phospholipids and diacylglycerols, respectively.
They are found primarily in the brain but are present in almost all human tissues [ 26 ]. Thus, endocannabinoids play a biological role in inflammation, insulin sensitivity, and fat and energy metabolism. In turn, endocannabinoid inhibitors may be precious tools for reducing the prevalence of metabolic syndrome. Furthermore, the modulation of the endocannabinoid system may display therapeutic potential for diverse chronic neurologic and immune conditions.
Anandamide N -arachidonoyl-ethanolamine AEA and 2-arachidonoylglycerol 2-AG are by far the most extensively investigated endocannabinoids. The pharmacological studies on these artificial cannabinoids have elucidated structure—activity relationships SARs and ECS metabolism [ 28 ]. Synthetic cannabinoids can be structurally related to THC or can have different scaffolds that do and do not contain heterocycle rings.
Most synthetic cannabinoids are lipid-soluble and apolar, consisting of 22—26 carbon atoms. Optimal activity requires more than four and up to nine saturated carbon atoms. Big efforts were made by John W. All of these products normally act as agonists or inverse agonists of CB 1 and CB 2 receptors, and may show alternate selectivity towards one of the receptor types.
This compound was synthesized by John W. It is a pyrazole derivative and is remarkably easy to synthesize [ 33 ]. SR was approved as an anorectic in Europe for the treatment of obesity, given its efficacy in decreasing appetite.
The FDA, however, refused its approval as anti-obesity drug because of the severe depression reported as a side effect. The cannabinoid receptors CB 1 and CB 2 comprise the endocannabinoid system ECS inside a cell, and the activation of these receptors is important for a number of physiological processes that regulate nervous, digestive, reproductive, immune, and metabolic functions [ 34 ]. There is growing body of evidence that the ECS system and synthetic cannabinoids modulate the activity of enzymes and nuclear factors involved in cancer cell homeostasis, growth, migration, metastasis, and tumor angiogenesis [ 1 , 35 - 38 ].
Remarkably, cannabinoids target cancer cells, while non-tumor cells and tissues are avoided. This apparent selectivity for tumor cells makes the ECS system an attractive potential target for cancer therapy. In , the natural cannabinoid THC was recognized as a potential anticancer agent [ 39 ], inhibiting lung adenocarcinoma cell growth in vitro and in vivo. Since that time, the therapeutic potential of cannabinoid for various types of cancer have been widely investigated [ 35 ]. Today, capsules of THC and its synthetic analogues have been approved for treating nausea and emesis associated with cancer chemotherapy [ 5 ].
In , the first human clinical study of THC was successfully performed in patients with recurrent glioblastoma multiforme [ 40 ]. The potential palliative effects of cannabinoids as appetite stimulators and pain inhibitors were also confirmed in phase III clinical trials in oncology [ 5 , 41 ]. Now, several plant-derived, synthetic, and endogenous cannabinoids that exert an antiproliferation effect on various cancers are widely recognized [Table 2 ].
Cannabinoid administration has been proven to slow tumor growth, as well as to slow lung carcinoma, prostate cancer, glioma, and skin carcinomas in mice [ 39 , 42 - 46 ]. Importantly, all of these studies found CB 1 receptors, CB 2 receptors, or both, which was later confirmed by molecular and pharmacological approaches that examined cannabinoid-receptor expression and used selective cannabinoid receptor agonists JWH and WIN 55, and antagonists such as AM and SRA.
The binding of cannabinoids to their G-protein-coupled cannabinoid receptors affects various cellular pathways, for example, it inhibits adenylate cyclase and activates extracellular-signal-regulated kinase ERK.
This suggests that cannabinoids might also be involved in other pathways important for cell survival, such as MAPK [ 47 ]. The activation of MAPK by cannabinoids has been observed in human vascular endothelial cells, neural cell lines, and Chinese hamster ovary cells [ 5 , 48 , 49 ]. The effect of cannabinoids on sphingomyelin breakdown, resulting in increased intracellular ceramide levels, has been also observed [ 52 ].
Finally, the activation of CB 1 or CB 2 receptors seems to induce apoptosis through de novo synthesis of ceramide in various types of cancer cells, including those associated with glioma, leukemia, colon, and pancreatic cancer [ 44 , 53 - 55 ]. The hallmark of cancer is the ability to proliferate despite the absence of mitogenic signals. Rapid proliferation of cancer cells requires large amounts of energy and oxygen; therefore, hypoxic cells secrete proangiogenic factors e. Thus, angiogenesis is one of the most important mechanisms through which solid tumors grow rapidly.
Currently, more attention is being paid to the mechanism of angiogenesis, mostly due to its correlation with cancer metastasis, and targeting antiangiogenic molecules has become the most promising therapeutic approach to cancer treatment. The range of known antiangiogenic factors is still growing; however, most treatment strategies are based on blocking signaling from vascular endothelial grow factors VEGFs , and especially, using blocking monoclonal antibodies for VEGFR1 and VEGFR2, such as Sunitinib or Bewacizumab [ 93 - 95 ].
Other treatment strategies target various steps in angiogenesis or degrade newly formed blood vessels. Cannabinoids have been proven to inhibit angiogenesis in in vivo and in vitro studies [ 38 ]. All tumors treated with JWH had a paler overall appearance and only very small and narrow capillaries forming differentiated and impermeable vascular networks compared to the controls.
Moreover, the authors showed that cannabinoid administration decreased vascular endothelial cell migration, survival, and expression of major proangiogenic factors such as VEGF, Ang-2, and MMP2 proteins [ 38 ]. Analysis of microarray data showed that JWH administration in C6 glioma-bearing mice induced altered expression of 10 genes directly or indirectly related to the VEGF pathway.
The same compounds were also efficient in the treatment of non-melanoma skin cancer by decreasing new blood vessel formation [ 46 , 97 ]. Matrix metalloproteinases MMPs are other possible molecular targets for cannabinoid treatment [ 98 ]. MMPs belong to the family of enzymes that participate in the degradation of the vascular basement membrane and remodeling of the extracellular matrix ECM [ 99 ].
This process sends one of the signals required for endothelial cells to migrate and form new blood vessels.
MMPs have been linked to tumor invasion and their increased expression is found in almost every type of cancer [ , ]. The MMP-2 level also decreased in biopsies obtained from patients with recurrent glioblastoma multiform after local administration of THC.
The influence of CB 1 and CB 2 activity on angiogenesis in cancer: After binding to a specific agonist, both CB 1 and CB 2 receptors are activated. This leads to direct and indirect changes that have crucial effects on angiogenesis in a cancerous environment. CB 1 receptor activation leads to the direct inhibition of VEGF type 2 receptors, which are major angiogenesis inducers.
Metalloproteinases production is stopped by the activation of both cannabinoid type 1 and type 2 receptors. Thus, all of these events have a direct impact on angiogenesis as well as the cell cycle and proliferation. Interactions between the various cell types observed within a tumor mass influence its development, progression, and metastasis. The composition of the microenvironment and roles of particular cells vary, depending on the tumor type and organ of origin.
These cells contribute to tumor development by secreting various pro-tumor factors or by inducing immunosuppression. One of the most important cell types to facilitate tumor development is tumor-associated macrophages TAMs [ - ].
TAMs are recruited into a tumor mass by various cytokines and chemokines secreted by cancer cells. Once they migrate to the tumor, they start to secrete various proangiogenic factors or enzymes that facilitate matrix remodeling. Indeed, chemoattractants secreted by cancer cells that increase the migratory abilities of immune cells and their infiltration to a tumor mass can also enhance cancer cell migration in an autocrine manner.
Due to the involvement of TAMs in cancer development, inhibition of their migration into a tumor mass has been proposed as one therapeutic approach [ ]. There are no published papers about the influence of cannabinoids on the tumor microenvironment and TAMs. However, the expression level of CB 2 receptors is considerably upregulated in activated macrophages [ ]. CB 2 receptors control several functions of macrophages, such as actin polymerization, migration, cell phenotype, and cytokine release from these cells [ ].
Cannabinoid ligands share receptors with important chemotactic cytokines that direct the migration of immune cells. These receptors are coupled to heterotrimeric Gi proteins [ ]. Because CCL5 is a very important ligand for G protein-coupled receptors CCR1 and CCR5, activation of the CB 2 leads to trans-deactivation of these receptors, which play specialized roles in leukocyte trafficking [ - ]. Additionally,cannabinoids, as highly lipophilic molecules, can perturb cellular membranes and alter ligand—receptor interaction, disrupt receptor-G protein complexes, and alter the cascade of signal transduction, thus decreasing the migratory abilities of cells [ - ].
Therefore, the regulatory function of cannabinoids on the tumor microenvironment needs further investigation. Renal cell carcinoma RCC represents a serious problem in oncology — it is the cause of over , deaths each year. RCC is the most common type of renal cell tumor, consisting of a substantial number of malignant cancers and benign tumors.
This type of cancer has a higher risk of appearance in males [ ]. The treatment of choice for renal cancers are nephrectomy combined with immunotherapy [ ], due to the high costs of other therapies or late detection.
However, novel drugs give hope to cancer patients — for example, therapies concerning the tyrosine kinase receptor inhibitor or multipurpose drugs targeting not only cancer cells but also stimulating the immune response. However, there is no perfect therapy for eliminating tumor cells.
Investigation of the anticancer properties of natural compounds, such as cannabinoids, have brought interesting results. Medical cannabis still remains a prescribed medication in some of therapeutic protocols and Cannabis sativa L. Cannabinoids also have an important influence on cancer cells themselves, what was mentioned before in this manuscript. There are many ways they inhibit tumor proliferation and survival. However, all of mechanisms are not identical in every cell and do not occur simultaneously.
Adenylyl cyclase is inhibited by the activation of both cannabinoid type 1 and type 2 receptors. Secreting apoptotic proteins, such as p27 and p21 via ceramide synthesis, speeds up the process of apoptosis. In the case of RCC, research is still lacking on cannabinoids as anticancer compounds. The expression of cannabinoid receptors CB 1 and CB 2 was first confirmed in the human proximal tubule HK2 cell line, and also lysate from rat kidney . Further studies are needed to help clarify these differences and the role of ECS in renal function.
Considering the specific cannabinoid receptors in kidneys, as well as the pro-apoptotic, antiproliferative, anti-metas-tatic and antiangiogenic effects of cannabinoids, this field should be explored.
Some results also suggest that patterns of cannabinoid receptor expression could be used in differential diagnosis of kidney cancers. These tumors originate from distinct sites in the kidney and show different molecular abnormalities. Interestingly, protein expression analysis of these RCC neoplasms failed to provide any evidence for the expression of CB 1 [ 36 , 86 ]. Thus, the CB 1 protein may undergo modifications in these tumors at the post-transcriptional level.
Therefore, further studies are required to understand the role of cannabinoids and their receptors in RCC. More research is needed to answer all questions about the potential use of cannabinoids to treat cancer. The first question is which type of cannabinoids should be used to treat cancer patients — natural or synthetic?
Different cannabinoids seem to have different effects on various cancer types, which may be caused by the different expression of cannabinoid receptors in various cancer types. Similarly, no studies have shown the effects of cannabinoids on the efficacy of chemotherapy. The psychoactive effect of cannabinoids should also be considered before its routine use. The authors acknowledge the support of the Scribendi, Inc.
National Center for Biotechnology Information , U. Published online Mar. Author information Article notes Copyright and License information Disclaimer. Received Oct 30; Accepted Dec This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.
This article has been cited by other articles in PMC. Abstract The endocannabinoid system ECS is a group of neuromodulatory lipids and their receptors, which are widely distributed in mammalian tissues.
Phytocannabinoids Phytocannabinoids are well-known natural products that are extracted and isolated from the Cannabis sativa L. Open in a separate window. The chemical structures of different classes of phytocannabinoids.
In each tissue, the ECS performs different tasks with the goal of maintaining The endocannabinoid system modulates the regulation of the. and possesses important regulatory functions throughout the bodies of Another primary endocannabinoid is 2-Arachidonoylglycerol (2-AG). The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, .. Evidence for the role of the endocannabinoid system in food-seeking . Other studies have found similar effects in endocannabinoid regulation of.