In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system. A. Cannabinoid Receptors and Ligands primarily in cells of the immune and hematopoietic systems (Munro et al., .. has been identified in our laboratory in RAW macrophages.
Cannabinoid Endocannabinoid Our Receptors System the and
Metabolic enzymes act like a natural referee in that they destroy endocannabinoids once they are used and no longer useful to the body. This self-regulating system ensures the interaction only happens when needed and therefore keeps the workings of the endocannabinoid system relatively quiet to the conscious brain, unlike, the hormonal system, which can keep the chemicals around longer than the interaction.
Because homeostasis is so important to health, all vertebrates and invertebrates are known to have an ECS. This discovery was quickly followed up with further evidence by Dr.
Raphael Mechoulam, the famous chemist who discovered THC. With less than 30 years of research, the endocannabinoid system is one of the less studied systems in the body.
Currently, restrictions on cannabis research limit what scientists can examine in terms of furthering our understanding of how cannabis interacts with the endocannabinoid system. When someone uses cannabis medicinally they are keying into these natural mechanisms which sometimes are deficient and need supplementation. Cannabinoid receptorsSo what do we know about how cannabis interacts with our bodies and the endocannabinoid system?
Two cannabinoid receptors have been discovered by researchers: CB1 is found in the central and peripheral nervous system. CB2 receptors are predominantly found in the immune system and the gastrointestinal system where they regulate inflammatory responses in the bowels.
CB2 receptors are also found in the brain, although not as densely as CB1 receptors. These receptors, a large part of the endocannabinoid system, play roles in regulating cardiovascular activity, appetite, mood, memory, and pain in the body. CBD stimulates both receptors and causes a reaction without binding directly, creating changes in cells that contain them. One other main endocannabinoid is 2-arachidonoylglycerol 2-AG which is active at both cannabinoid receptors, along with its own mimetic phytocannabinoid, CBD.
The neurons , neural pathways , and other cells where these molecules, enzymes, and one or both cannabinoid receptor types are all colocalized collectively comprise the endocannabinoid system. The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed that cannabinoids act as neuromodulators    for a variety of processes, including motor learning ,  appetite ,  and pain sensation,  among other cognitive and physical processes.
The localization of the CB1 receptor in the endocannabinoid system has a very large degree of overlap with the orexinergic projection system , which mediates many of the same functions, both physical and cognitive. Cannabinoid binding sites exist throughout the central and peripheral nervous systems.
The two most relevant receptors for cannabinoids are the CB 1 and CB 2 receptors, which are expressed predominantly in the brain and immune system respectively. For example, in rodents, the highest concentration of cannabinoid binding sites are in the basal ganglia and cerebellum , regions of the brain involved in the initiation and coordination of movement.
A recent analysis of cannabinoid binding in CB 1 and CB 2 receptor knockout mice found cannabinoid responsiveness even when these receptors were not being expressed, indicating that an additional binding receptor may be present in the brain. CB1 has also been noted to form a functional human receptor heterodimer in orexin neurons with OX1 , the CB1—OX1 receptor, which mediates feeding behavior and certain physical processes such as cannabinoid-induced pressor responses which are known to occur through signaling in the rostral ventrolateral medulla.
During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the synaptic cleft which bind to cognate receptors expressed on the post-synaptic neuron.
Based upon the interaction between the transmitter and receptor, neurotransmitters may trigger a variety of effects in the post-synaptic cell, such as excitation, inhibition, or the initiation of second messenger cascades.
Based on the cell, these effects may result in the on-site synthesis of endogenous cannabinoids anandamide or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium.
This exclusion is based on synthesis-specific channel activation: Evidence suggests that the depolarization-induced influx of calcium into the post-synaptic neuron causes the activation of an enzyme called transacylase.
This enzyme is suggested to catalyze the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine , a membrane-resident phospholipid, into N -acyl-phosphatidylethanolamine NAPE. Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial cell inactivation. Endocannabinoids are taken up by a transporter on the glial cell and degraded by fatty acid amide hydrolase FAAH , which cleaves anandamide into arachidonic acid and ethanolamine or monoacylglycerol lipase MAGL , and 2-AG into arachidonic acid and glycerol.
Such approaches could lead to the development of new drugs with analgesic, anxiolytic-like and antidepressant-like effects, which are not accompanied by overt signs of abuse liability. Cannabinoid receptors are G-protein coupled receptors located on the pre-synaptic membrane.
While there have been some papers that have linked concurrent stimulation of dopamine and CB 1 receptors to an acute rise in cyclic adenosine monophosphate cAMP production, it is generally accepted that CB 1 activation via cannabinoids causes a decrease in cAMP concentration by inhibition of adenylyl cyclase and a rise in the concentration of mitogen-activated protein kinase MAP kinase.
Results from rat hippocampal gene chip data after acute administration of tetrahydrocannabinol THC showed an increase in the expression of transcripts encoding myelin basic protein , endoplasmic proteins, cytochrome oxidase , and two cell adhesion molecules: In addition, CB1 activation has been demonstrated to increase the activity of transcription factors like c-Fos and Krox Graham et al.
The molecular mechanisms of CB 1 -mediated changes to the membrane voltage have also been studied in detail. Recent studies have found that CB 1 activation specifically facilitates potassium ion flux through GIRKs , a family of potassium channels. In the central nervous system , CB 1 receptors influence neuronal excitability, reducing the incoming synaptic input.
CB 1 receptors then reduce the amount of neurotransmitter released, so that subsequent excitation in the presynaptic neuron results in diminished effects on the postsynaptic neuron. It is likely that presynaptic inhibition uses many of the same ion channel mechanisms listed above, although recent evidence has shown that CB 1 receptors can also regulate neurotransmitter release by a non-ion channel mechanism, i.
Mice treated with tetrahydrocannabinol THC show suppression of long-term potentiation in the hippocampus, a process that is essential for the formation and storage of long-term memory. One study found that the high-dose treatment of rats with the synthetic cannabinoid HU over several weeks resulted in stimulation of neural growth in the rats' hippocampus region, a part of the limbic system playing a part in the formation of declarative and spatial memories , but did not investigate the effects on short-term or long-term memory.
In the adult brain, the endocannabinoid system facilitates the neurogenesis of hippocampal granule cells. The inhibitory effects of cannabinoid receptor stimulation on neurotransmitter release have caused this system to be connected to various forms of depressant plasticity. A recent study conducted with the bed nucleus of the stria terminalis found that the endurance of the depressant effects was mediated by two different signaling pathways based on the type of receptor activated.
Similar post-synaptic receptor dependencies were found in the striatum, but here both effects relied on presynaptic CB 1 receptors. By selectively internalizing different receptors, the brain may limit the production of specific endocannabinoids to favor a time scale in accordance with its needs. Evidence for the role of the endocannabinoid system in food-seeking behavior comes from a variety of cannabinoid studies. Emerging data suggests that THC acts via CB 1 receptors in the hypothalamic nuclei to directly increase appetite.
The amount of endocannabinoids produced is inversely correlated with the amount of leptin in the blood. A related study examined the effect of THC on the hedonic pleasure value of food and found enhanced dopamine release in the nucleus accumbens and increased pleasure-related behavior after administration of a sucrose solution. While there is need for more research, these results suggest that cannabinoid activity in the hypothalamus and nucleus accumbens is related to appetitive, food-seeking behavior.
The endocannabinoid system has been shown to have a homeostatic role by controlling several metabolic functions, such as energy storage and nutrient transport. It acts on peripheral tissues such as adipocytes , hepatocytes , the gastrointestinal tract , the skeletal muscles and the endocrine pancreas. It has also been implied in modulating insulin sensitivity.
Through all of this, the endocannabinoid system may play a role in clinical conditions, such as obesity , diabetes , and atherosclerosis , which may also give it a cardiovascular role. While the secretion of glucocorticoids in response to stressful stimuli is an adaptive response necessary for an organism to respond appropriately to a stressor, persistent secretion may be harmful.
The endocannabinoid system has been implicated in the habituation of the hypothalamic-pituitary-adrenal axis HPA axis to repeated exposure to restraint stress. Studies have demonstrated differential synthesis of anandamide and 2-AG during tonic stress. A decrease of anandamide was found along the axis that contributed to basal hypersecretion of corticosterone ; in contrast, an increase of 2-AG was found in the amygdala after repeated stress, which was negatively correlated to magnitude of the corticosterone response.
All effects were abolished by the CB 1 antagonist AM , supporting the conclusion that these effects were cannabinoid-receptor dependent. These contrasting effects reveal the importance of the endocannabinoid system in regulating anxiety -dependent behavior.
Results suggest that glutamatergic cannabinoid receptors are not only responsible for mediating aggression, but produce an anxiolytic-like function by inhibiting excessive arousal: In addition, the activation of the CB1R has been reported to be beneficial in AD animal models with memory deficits and cognitive disorders [ , , ].
In , decreased expression of the CB1R was first reported in the substantia nigra of HD patients via autoradiography [ ]. Further studies revealed a progressive loss of CB1Rs as an early sign of HD, which occurred before the onset of actual neurodegeneration, and hastened the worsening of HD [ ]. A recent study described downregulation of the CB1R not only in medium spiny projection neurons MSNs but also in a subpopulation of interneurons that are selectively preserved in both transgenic HD mice and HD patients [ ].
Administration of THC has been reported to ameliorate motor disorders, striatal atrophy, and Htt aggregates in transgenic mice, although controversy exists [ , ].
These observations support a critical and possibly beneficial role of the CB1R in neurodegenerative diseases. The historical record of the anti-epileptic effects of the CB1R dates back centuries [ 1 ]. Case reports on the beneficial effects of cannabinoids on epileptic patients became available only after the identification of THC [ , ]. However, studies also suggested increased seizure frequency after marijuana smoking [ ].
This paradoxical effect of cannabinoids on epilepsy is not only seen in human studies but has also been reported in animal models [ , ]. The alteration of the endocannabinoid system following epilepsy is cell type-specific.
This concept is supported by previous animal studies showing that CB1R retrograde signaling is selectively enhanced at inhibitory but not excitatory synapses, resulting a persistent potentiation of DSI but not DSE in febrile seizures, which leads to hyper-excitability of neurons, thus contributing to the exacerbation of seizures [ , ].
Moreover, this CB1R-mediated enhanced suppression of inhibitory neurons is phase-dependent as well. Hippocampal tissues from epileptic patients in the acute phase of epilepsy display decreased CB1R density, especially in the dentate gyrus, whereas in patients in the chronic phase of epilepsy, an upregulation of CB1R has been observed [ , , , ].
Despite the low expression of CB1R in hypothalamus, cannabinoids are long known for their effects to stimulate appetite, prominently in a CB1R-dependent manner [ ]. Endocannabinoids levels are increased in the rat hypothalamus during fasting and return to normal levels after food consumption [ ].
The stimulation of appetite and feeding behavior is observed after direct injection of endocannabinoids and is abolished by the administration of CB1R antagonists [ ]. Furthermore, activation of ventral striatal CB1Rs inhibit GABAergic neurons, resulting in a hypophagic but not an orexinergic effect [ ]. In addition to the hypothalamus, olfactory process have been proposed to be involved in the positive regulation of CB1R-mediated food intake [ ]. Moreover, crosstalk between CB1Rs and the important hormones involved in appetite regulation, including ghrelin, leptin, and orexin, has been extensively reported [ 68 , ].
CB1Rs expressed in the GI tract also are involved in metabolic process and energy balance, as discussed in the previous section. These studies suggest that CB1R-mediated regulation of appetite involves at least two aspects: Rimonabant, a CB1R antagonist, displayed remarkable anti-obesity effects, yet the accompanying psychiatric side effects lead to its withdrawal from the market [ ].
An up-to-date review by Koch have summarized the recent progress on elucidating the role of CB1R in appetite control [ ]. The regulation of pain is one of the earliest medical applications of cannabinoids [ 1 , 2 ]. Numerous studies have documented the analgesic effects of cannabinoids in different types of pain, including chemical, mechanical, and heat pain, as well as neuropathic, inflammatory, and cancer pain [ , ]. The endocannabinoid system also is involved in the regulation of nociception [ 3 ].
A newly published review paper has discussed the preclinical and clinical studies on the role of endocannabinoids in the control of inflammatory and neuropathic pain in details [ ]. Furthermore, the phytocannabinoids have drawn much attention nowadays in the field of antinociception and other neurological disorders.
CBD, for instance, has been shown to modulate chronic pain in several studies [ ]. The drug with brand name Sativex, containing equal amount of THC and CBD, is used to treat several kinds of multiple sclerosis associated symptoms including chronic pain [ ].
Cannabinoids used in cancer are best-known for their palliative effects, including reducing nausea and vomiting, alleviating cancer pain, and stimulating appetite [ , ]. It has been argued that cannabinoids can exert anti-tumor effects directly through the inhibition of cell proliferation and induction of apoptosis, or indirectly through the inhibition of angiogenesis, invasion and metastasis [ ].
The antitumor effects of cannabinoids have also been observed in various animal tumor models [ ]. In general, an enhanced endocannabinoid system is seen in tumor tissues [ , , ]. However, the role of upregulated endocannabinoid system activity is still controversial as contrasting results have been reported supporting a proliferative as well as an anti-proliferative role of cannabinoids on cancer cells [ , ].
Interestingly, a bimodal effect of cannabinoids on cancer cell growth has also been observed, with low concentrations being proliferative and high concentrations being pro-apoptotic [ ]. Most cannabinoid-base drugs available now in market are THC derivatives, indicated for anorexia and emesis associated with chemotherapy [ ]. As a result of systematic activation of the CB1R, the accompanying side effects always include cardiovascular dysfunction, digestion failure, neurological disorders and potential for addiction [ ].
The goal of cannabinoid-based drugs is to fully explore their promising therapeutic potentials without these adverse effects and the success of Sativex provides some insights. First, phytocannabinoids may block the undesired psychoactive effects of compounds targeting CB1R. Although the exact mechanism of how a 1: Second, phytocannabinoids alone possess great potential as drug targets. Excluding THC, all phytocannabinoids identified so far are non-psychoactive, making them a safer choice and a great pool for drug screening.
Encouraging results have been reported on their therapeutic potential in various diseases [ 15 , 17 ]. Research has progressed significantly towards this direction in the past few years, with several synthetic or natural compounds characterized as CB1R allosteric ligands [ , , , ]. A detailed review on their pharmacological properties and therapeutic potentials is available [ ]. CB1R has been shown to heterodimerize with several GPCRs, with distinct pharmacological properties, emphasizing its significance in different pathological conditions [ , ].
Efforts have been made to utilize these findings in drug discovery focusing on specific heterodimer complex, although recent findings on the structures of CB1R and other lipid-binding receptor suggest that the currently available bivalent ligands targeting CB1R homo- or heterodimers are unlikely to bind both protomers simultaneously [ , ].
More information on CB1R structure and dimerization interface is needed for better design of bivalent and dualsteric ligands. Besides CB1R, other elements in the endocannabinoid system have become targets of drug discovery as well.
Inhibitors of enzymes that degrade endocannabinoids, such as FAAH inhibitors, work effectively as an alternative way of CB1R activation and endocannabinoid tone enhancement, although caution should be taken in the use of these drugs due to their potential off-target activities [ ].
On the other hand, CB2R is also attracting more interest, especially on the peripheral sites, where studies have shown its beneficial effects in various pathological conditions [ 55 ].
Also, recent studies have discovered its presence and significance in the CNS, revealing another exciting therapeutic potential of CB2R [ 56 ]. The initial discovery and subsequent intensive research of the endocannabinoid system in the last three decades have revealed probably the most well-known retrograde neurotransmission system.
Its widespread expression and versatile functions not only support its promising potential as a drug target for various diseases, but also make the undesired side effects almost inevitable.
Moreover, as a neuromodulator, the crosstalk between endocannabinoid and other neurotransmitter systems, via either local neural circuits, or receptor heteromerization, or downstream signaling, has been emphasized. Fruitful studies have been generated, unraveling the complexity of the whole endocannabinoid system. It is critical to keep in mind that the study of the endocannabinoid system should be region- and condition-specific, along with the consideration of other neurotransmission systems.
National Center for Biotechnology Information , U. Int J Mol Sci. Published online Mar Author information Article notes Copyright and License information Disclaimer. Received Feb 9; Accepted Mar This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution CC BY license http: This article has been cited by other articles in PMC. Abstract The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa marijuana are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 CB1R and 2.
Introduction The plant Cannabis sativa , better known as marijuana, has long been used for medical purpose throughout human history. Cannabinoid Receptors Due to the lipophilic nature of cannabinoids, it was initially thought that these compounds exert various biological effects by disrupting the cell membrane nonspecifically. Endocannabinoid System The successful identification and cloning of the CB1R prompted the discovery of its first endogenous agonist, AEA, in [ 13 ]. Open in a separate window.
Physiological and Pathological Roles of the CB1R Given the widespread distribution of CB1Rs in the human body, it is reasonable for one to speculate a broad spectrum of physiological roles of the CB1R [ 3 , 9 , 63 , ]. Future Directions of Cannabinoid-Based Drug Discovery Most cannabinoid-base drugs available now in market are THC derivatives, indicated for anorexia and emesis associated with chemotherapy [ ]. Conclusions The initial discovery and subsequent intensive research of the endocannabinoid system in the last three decades have revealed probably the most well-known retrograde neurotransmission system.
Author Contributions Shenglong Zou wrote the manuscript. Ujendra Kumar edited the manuscript. Conflicts of Interest The authors declare no conflict of interest. The Science of Marijuana. The endocannabinoid system as an emerging target of pharmacotherapy.
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The Endocannabinoid System
Endocannabinoids; Receptors in the nervous system and around your body that endocannabinoids and cannabinoids bond with; Enzymes that. The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, The cannabinoid receptors CB1 and CB2, two G protein- coupled receptors that The localization of the CB1 receptor in the endocannabinoid system has a very Further, our studies established the dependence of the central. Did you know that there is a system in our bodies comprised of receptors that interact exclusively with cannabinoids like CBD and THC?.