Summary of Conditions Affected by Cannabinoids and the Endocannabinoid System The upregulation of the endocannabinoid system with THC and CBD, for. Ever wonder how cannabinoids interact with your body? The answer is through the endocannabinoid system, which keeps our to decrease pain, fight cancer, prevent neurodegenerative diseases, and promote health. We aim to define several potential roles of cannabinoid receptors in . In brief, AEA is catalyzed from N-acyl-phosphatidylethanolamine . in the cardiovascular system under pathological conditions, which in Ellison J.M., Gelwan E., Ogletree J. Complex partial seizure symptoms affected by marijuana.
and by Affected the Cannabinoids Endocannabinoid System of Summary Conditions
MS has accompanied human beings for about years, time in which the disorder has been target of enormous endeavors that have aimed to describe and understand the underlying mechanisms. In regard to the causes that lead to this illness, strong evidence indicates that a particular genotype plus environmental or somewhat random stimulus may led individuals more prone to develop the disorder [ 5 , 28 , 29 ].
MS patients experience immune attack to the CNS, exerting acute damage to the glial cells that form myelin, the oligodendrocytes. In addition, the autoimmune acute inflammation can be spotted along brain matter and meninges. In this form, loss of neurons is eventually reached as the demyelination process turns chronic and is convoyed by severe degeneration of axons; as expected, neuronal loss is linked with the disability manifested throughout the disease, a condition that lessens dramatically the quality of life of patients.
MS can portray neuronal dysfunction, and states of accumulated or irreversible disability, and even some cases exhibit both [ 30 ]. Consequently, the distressing outcome that characterizes MS has drawn the attention of the medical fields in order to improve the quality of life of patients who endure it through valid therapeutic options; unfortunately, the etiology remains unknown, and to this date, there is no definite treatment.
Moreover, despite a myriad of efforts and even after a century of awareness and constant research, MS therapeutics still face major challenges as a proper diagnose is hard to meet given the lack of a leading and straightforward test that prevents from missed and incorrect diagnoses. Thus, while we face the lack of a cure or effective treatment, research has offered several disease-modifying drugs DMDs , which help reducing MS activity and improve the overall course of the disease.
Approved treatments for MS are diverse and include glatiramer acetate, immunomodulatory compound approved by the FDA for the reduction of the frequency of relapses of MS and, however, does not reduce progression of disability; on the other hand, mitoxantrone is an antineoplastic agent that has shown effectiveness in slowing the progression of secondary-progressive MS, a stage of the disease that follows the relapsing—remitting disease course; although this therapy provides some benefit, the use of agents of this nature carries several adverse reaction of varying severity, which limits usage in MS patients; lastly fingolimod, a selective immunosuppressive drug currently approved in the United States as a first-line treatment, or otherwise approved in countries of the European Union as a second-line treatment given safety clauses [ 30 ].
The previously stated therapies are effective to some extent and mainly regulate the immune system activity but have no competence to repair immune-mediated damage to the myelin sheaths, turning them worthless for neurodegenerative scenarios.
Alternatively, with remyelination therapies, neuronal function can be restored, and some future neuronal loss can be prevented. A therapy of this class is substantiated with the proposal that a treatment that enhances remyelination might be even more effective in reducing long-term disability due to the increase in neuronal survival.
For these purposes, monoclonal antibodies such as alemtuzumab and BIIB are few examples of novel attempts on the mater, and so far, the promotion of remyelination has proven to reduce overall clinical severity in animal models of the disease [ 31 ]. Despite moving towards clinical studies, several factors have been found to contribute to failure of the approach, as sporadically oligodendrocytes do not remyelinate axons effectively; moreover, oligodendrocyte precursor cells OPC are not always recruited into the lesions at functional levels [ 28 , 31 ].
With an indefinite pathogenesis, ALS is known to comprise environmental and genetic factors. As expected, the assessment of the environmental factors that may be associated to the disease is imperative; however, many more studies from different sources are needed to judge appropriately such relationship and determine accurately the risk factors that come along with it.
Early diagnosis of ALS is based mainly on the neurologist judgment of clinical signs and symptoms and constitutes a crucial element to ensure quality of life; nevertheless, diagnosis is often met a year, or up to 3 years, before the first symptoms, creating an obstacle to adequate medical care.
Besides, very few therapeutic alternatives are currently licensed as treatment for the ALS; a great example is riluzole, a potent inhibitor of glutamate release used recurrently to delay the onset of particular symptoms, but which does not result in substantial benefit in terms of therapeutic effects.
Still, emerging evidence indicates that numerous factors may contribute strongly with the degenerative process of the disorder; primarily, the influence of enhanced oxidative stress and neuroinflammation events, which is also hypothesized as causative agents for other high-incidence diseases such as AD or PD; additionally, glutamate toxicity, mitochondrial dysfunction, or excessive apoptosis contribute actively to the progression of the disease and entail the basis of proposed therapies to delay neural loss and prolong cell survival [ 32 — 36 ].
Likewise, numerous evidence is implicating the receptor for advanced glycation end-products, or RAGE, as part of the genesis of several disorders. RAGE is known to be part of cell surface immunoglobulins, and its role as a factor of oxidative stress, inflammation, and cellular detriment in neurodegenerative diseases is gaining attention over the years. The precise mechanisms underlying the involvement of RAGE in neurodegeneration and its detrimental effects remain unknown, and yet some studies have provided valuable suggestions of RAGE as a crucial contributor of the pathogenesis of ALS; of special interest are those works that demonstrate the upregulation of AGE receptors and its ligands, revealing an interesting trace to further look into on experimental approaches [ 33 ].
In this form, many more hypotheses and experiments are needed to reach definite understanding of the etiopathogenesis of ALS. Organic acid disorders are autosomal-recessive inherited metabolic disorders that appear as a result of an aberrant step in the catabolic route of branched-chain amino acids, usually the consequence of deficient enzyme activity.
In this form, organic acids tend to accumulate in fluids and tissues, followed by various pathological effects such as overdosage of toxic chemical compounds, as well as shortage of essential compounds omitted with the interruption of inner pathways. A recurrent clinical manifestation of such disorders comprises encephalopathy, which consist of neurologic symptoms as seizures, lethargy, and malnutrition, all of which progress over time and lead to coma.
In this way, those who endure it often present acute symptoms early in life; prompt diagnosis is thus a crucial element to avoid irreversible brain damage, as lack, tardy, or incorrect treatment would lead to low quality of life and permanent neurological consequences. Likewise, several organizations working towards the awareness and understanding of metabolic diseases have emphasized the importance of prenatal diagnosis for cases with elevated risk factors through the analysis of amniotic fluid, enzyme activity, or DNA testing.
Such efforts have thrown some sampling and tests that have been useful for this purpose, such as very long chain fatty acids or lysosomal enzymes; however, the elevated costs along with the lack of consciousness of the implied consequences have slowed the progress in the matter. The hereditary element of the disease signalizes the increased number of risk factors of offspring presenting an OAs; in this form, as OAs are considered rare, adequate assessment of the prevalence of the disease would need to rely on rigorous and periodic reports; however, the reportage of its presence among the population is irregular.
Thereby, high prevalence has been theorized in Porto Alegre, Brazil, and South Indian regions, as well as some Western countries; in addition, several cases have been followed closely at health institutions from Damascus, Syria. Luckily, the elevated presence of these disorders over the past 20 years increased noticeably the efforts towards its study. So that the diagnostic elements and clinical features of these disorders of metabolic nature are increasingly being documented.
Considering the poor prognosis faced by patients, lots of efforts have been placed into the treatment of the manifestations of these disorders. Options imply the restoration of the biochemical homeostasis in regard to the specific aberrant element, usually through complete treatment schedules of dietary restriction of the precursor amino acids, administration of adjunctive compounds to dispose the toxic metabolites, or enhancement of the deficient enzymes.
Additionally, patients often require liver transplantation given the high demand on this organ; however, only a minority has access to such alternatives, and even less patients find success with this alternative [ 37 — 40 ]. In spite of its concrete aberrations, search of new clinical options has reached this neurometabolic disorders. Along with the accumulation of several metabolites, including glutaric, methylmalonic, and propionic acid, a severe neurodegenerative process takes place in OAs brain of children; the latter, as known, is associated with many other damage mechanisms from oxidative stress to excitotoxicity.
In this form, the benefits and multiple advantages or proposed neuroprotective therapies could provide invaluable input for such disorders. The ECS has been formally recognized as such for around 20 years, and its study has yielded information that reveals the close relationship of this system in the brain. As known, type 1 cannabinoid receptors CB1r are widely expressed within the CNS, in particular in the motor cortex, thalamus, hypothalamus, and hippocampus to name a few.
On the other hand, type 2 cannabinoid receptors CB2r are found in the CNS as well as peripheral tissue. Cannabinoid circuitry is associated with a number of physiological processes, as endogenous cannabinoids such as 2-arachidonoyl glycerol 2-AG or anandamide AEA interact with the G-protein-coupled receptors, CB1r and CB2r, and are known to regulate the neurotransmitter-release inhibition through the adenylate cyclase inhibition [ 41 ].
Given the foregoing in regard to the current status of AD and its therapeutics, the high density of CB1r in the basal ganglia tipped the balance towards a scenario in which particularly this receptor could provide evidence that highlight the therapeutic potential of the ECS in the AD.
Moreover, subpopulations of the CB1r located at the hippocampus are well-known to contribute to the effect in memory and learning, processes that face great detriment during the progression of AD and are also features of the AD brain [ 42 ]. It is strongly suggested that cannabinoids hold anti-inflammatory and antioxidant properties that result in an overall neuroprotective effect; this is hypothesized to occur through the promotion of several intrinsic repair mechanisms able to reduce oxidative stress or apoptotic events.
Neuronal damage is known to trigger the endogenous production of cannabinoids such as AEA [ 43 ]. On the other hand, CB2r is also of interest, and so far, its anti-inflammatory properties and neurogenesis stimulation have been proven as well. In conclusion, the promissory potential of the ECS satisfies the demands of a neurodegenerative condition with no cure or adequate treatment to this date.
The abovementioned strategies represent interesting actions of the cannabinoids; until now, the manipulation of the ECS has yielded promising results and might be more efficient than the present choices.
In this way, the AD therapeutics strongly call for further research to demonstrate conclusively such properties, in order to respond accordingly to the needs of those who endure it. On the other hand, current pharmacological therapy in PD relies on formulations unable to attain suitable efficiency; in response to this condition, the potential of cannabinoid compounds has attracted attention to the field, as well as the possible applications with countless clinic value.
As known, cannabinoid receptors are currently being associated to a number of neuropathogenic processes as various reports affirm that such molecules may act as ideal means for pathologies with inflammatory components.
Furthermore, increasing evidence has disclosed that ECS goes through a number of alterations during brain disorders and PD is not an exception. To this point, it is known that dopamine depletion imposes great impact into the ECS and causes an upregulation of the CB1r and endocannabinoids in basal ganglia, which of course fundaments the multiple hypothesis regarding cannabinoid applications.
In fact, published data states that an early pre-symptomatic phase in PD would display desensitization or downregulation of CB1r, and which ultimately lead to excitotoxicity, oxidative stress, and inflammatory events; on the other hand, advanced phases of the disease would exhibit upregulation of CB1r consistently with the hyperkinesia manifested by patients [ 18 ]; in this form, the opportunity area in the different stages is evident. The reader will find an extensive list of recent reviews that explore the physiological relevance of the endogenous cannabinoid system, as depicted in Table 1.
In this section, we focus on the cellular and system physiological events mediated by endocannabinoids that are relevant to our understanding of the contribution of the endogenous cannabinoid system in alcoholism. As described in the section on biochemistry of the endogenous cannabinoid system, endocannabinoids are released upon demand after cellular depolarization or receptor stimulation in a calcium-dependent manner. Once produced, they act on the cannabinoid receptors located in the cells surrounding the site of production.
This property indicates that endocannabinoids are local mediators similar to the autacoids e. In the CNS, the highly organized distribution of endocannabinoid signalling elements in GABAergic and glutamatergic synapses and their preservation throughout evolution suggests a pivotal role in synaptic transmission.
If endocannabinoids act postsynaptically they will counteract the activatory inputs entering the postsynaptic cells. This mechanism has been proposed for postsynaptic interactions with dopaminergic transmission Felder et al.
Despite its importance, this effect is secondary to the important presynaptic actions whose existence is supported by two facts: Presynaptic inhibition of transmitter release by endocannabinoids may adopt two different forms of short-term synaptic plasticity, depending on the involvement of GABA or glutamate transmission, respectively: Both forms of synaptic plasticity involve the initial activation of a postsynaptic large projecting neuron pyramidal or Purkinje cells that sends a retrograde messenger to a presynaptic GABA terminal DSI or a presynaptic glutamate terminal DSE , inducing a transient suppression of either the presynaptic inhibitory or the presynaptic excitatory input.
The contribution of endocannabinoids to these forms of short-term synaptic plasticity has been described in the hippocampus Wilson and Nicoll, ; Wilson et al. The nature of the endocannabinoid system acting as a retrograde messenger is still unknown.
The role of endocannabinoid-induced DSI or DSE seems to be the coordination of neural networks within the hippocampus and the cerebellum that are involved in relevant physiological processes, such as memory or motor coordination. Additional forms of endocannabinoid modulation of synaptic transmission involve the induction of long-term synaptic plasticity, namely long-term potentiation LTP and long-term depression LTD.
Both forms of synaptic plasticity involve long-term changes in the efficacy of synaptic transmission in glutamatergic neurons, which have a major impact on consolidation and remodelling of the synapsis. Activation of the cannabinoid receptors prevents the induction of LTP in the hippocampal synapses Stella et al.
Overall, endocannabinoids act as local messengers that adjust synaptic weight and contribute significantly to the elimination of information flow through specific synapses in a wide range of time frames. The fact that cannabinoid receptor stimulation has a major impact on second messengers involved not only in synaptic remodelling Derkinderen et al.
Both processes are relevant for homeostatic behaviour such as motivated behaviour feeding, reproduction, relaxation, sleep and emotions, as well as for cognition, since learning and memory require dynamic functional and morphologic changes in brain circuits.
An experimental confirmation of this hypothetical role of the endogenous cannabinoid system was the demonstration of its role in the control of the extinction of aversive memories Marsicano et al. The cellular effects of endogenous cannabinoids have a profound impact on the main physiological systems that control body functions Table 1.
Despite the peripheral modulation of the immune system, vascular beds, reproductive organs, gastrointestinal motility and metabolism, the endogenous cannabinoid system tightly regulates perception processes including nociception cannabinoids are potent analgetics, Martin and Litchman, and visual processing in the retina Straiker et al. Additional functions exerted by the endogenous cannabinoid system involve the regulation of basal ganglia and cerebellar circuits, where it is involved in the modulation of implicit learning of motor routines Rodriguez de Fonseca et al.
Among the varied functions in which the endogenous cannabinoid system is engaged, the homeostatic control of emotions and the regulation of motivated behaviour merit special attention because of its impact on human diseases, including addiction. The endogenous cannabinoid system controls the motivation for appetite stimuli, including food and drugs Di Marzo et al.
The positive effects of endocannabinoids on motivation seem to be mediated not only by the peripheral sensory systems in which cannabinoid receptors are present i. The endogenous cannabinoid system is widely distributed in the extended amygdala, a set of telencephalic nuclei located in medial septal neurons, the nucleus accumbens shell and amygdalar complex, and are involved in the control of motivated behaviour, conditioned responses and gating-associated emotional responses.
This hypothesis is supported by two facts: Research on the neurobiological basis of endocannabinoid effects on motivated behaviour has focused on endocannabinoid—dopamine interaction as well as on the role of the endocannabinoid system in habit learning and conditioning. Most drugs of dependence activate the VTA dopaminergic neurons, as monitored by the dopamine release in terminal areas, especially in the nucleus accumbens and prefrontal cortex, or by the firing rates of VTA dopaminergic neurons.
THC and other CB 1 receptor agonists increase dopamine efflux in the nucleus accumbens and prefrontal cortex and increase the dopaminergic cell firing in the VTA for review see Gardner and Vorel, This effect is not caused by the direct activation of dopaminergic neurons because they do not express CB 1 receptors Julian et al.
Although the effects of cannabinoid agonists on dopamine release in the projecting areas i. This discrepancy may suggest the existence of a differential role for endogenous opioid systems as the modulators of cannabinoid actions in dopamine cell bodies with respect to their axon terminals.
In agreement with these actions of cannabinoids in brain reward circuits, repeated cannabinoid exposure can induce behavioural sensitization similar to that produced by other drugs of dependence.
Interestingly, administration of a CB 1 receptor antagonist blocks cue-induced reinstatement to heroin and cocaine self-administration De Vries et al. The importance of the endogenous cannabinoid system in the control of motivated behaviour goes far beyond the control of processing ongoing reward signals.
The CB 1 receptors are apparently involved in the control of reward homeostasis Sanchis-Segura et al. Moreover, when cannabinoid homeostatic mechanisms are not adequate to restore the lost equilibrium in reward control derived from continuous uncontrolled exposure to a reinforcer e. This has been demonstrated in rodents exposed to cycles of dependence—abstinence to alcohol and morphine Navarro et al. Whether these allostatic changes occur in other models of motivated behaviour i.
Cannabinoid receptors are not only associated with motivational disturbances, but also related to emotional processing. A key station for the endocannabinoid regulation of emotions is the amygdalar complex. The final balance will lead to anxiety or anxiolysis, depending on the rate of activation of descending projections of the central nucleus of the amygdala to the hypothalamus endocrine responses and brain stem behavioural and autonomic responses. However, recent studies indicate that anxiolysis is the normal response to enhanced cannabinoid transmission in the limbic system, as reflected by the phenotype of FAAH knockout mice and the effects of FAAH inhibitors Cravatt et al.
The induction of anxiety by cannabinoid receptor antagonists Navarro et al. The presence of the endogenous cannabinoid system in reward circuits and its role in motivational and emotional homeostasis suggests that drugs which modulate cannabinoid signalling might serve as therapeutic tools in drug addiction. In accordance with this rationale, the CB 1 receptor antagonists are able to modulate opioid self-administration in rodents Navarro et al.
Extending this hypothesis, converging research lines have established a role for both anandamide and the CB 1 receptor in alcohol dependence Hungund and Basaravajappa, ; Hungund et al. The administration of CB 1 receptor agonists promotes alcohol intake Colombo et al. Molecular studies have shown that chronic alcohol administration is associated with an increased formation of both anandamide and its membrane precursor NAPE Basavarajappa and Hungund, Chronic alcohol exposure also resulted in the stimulation of a second endocannabinoid, 2-AG Basavarajappa et al.
Animal studies also revealed that chronic exposure to alcohol downregulated the CB 1 receptors in the brain Basavarajappa et al. Finally, a recent gene screening study has identified the CB 1 receptor as one of the genes whose expression is permanently affected by serial cycles of alcohol dependence and withdrawal Rimondini et al.
These data indicate a role for the endogenous cannabinoid system as a relevant contributor to alcoholism. In the present issue, the reader will find additional experimental approaches to the role of the endogenous cannabinoid system in alcoholism. Since the discovery of anandamide, the increasing information on the physiological roles played by the endogenous cannabinoid system and its contribution to pathology have led to this signalling system becoming more important in neurobiology.
The intense pharmacological research based on this information has yielded, in a very short time, potent, selective drugs targeting the endogenous cannabinoid system that have opened up new avenues for the understanding and treatment of major diseases including cancer, pain, neurodegeneration, anxiety and addiction.
This is a very promising starting point for a new age that takes over from the ancient use of Cannabis as a medicine. Now is the time for clinical trials aimed at evaluating the efficacy of cannabinoid drugs in disorders lacking effective therapeutic approaches, such as alcoholism. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account.
Close mobile search navigation Article navigation. A correction has been published: Abstract The endogenous cannabinoid system is an ubiquitous lipid signalling system that appeared early in evolution and which has important regulatory functions throughout the body in all vertebrates.
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There are lots of different types of receptors, and where and when they exist can vary by cell type and other cellular activity. The location of the receptors and the specificity of that message to that receptor will greatly impact the function of the message. Think of this a bit like a lock and key. But, on the other hand, a key that might open both your front and back doors could be useful in some circumstances. In fact, the reason why it was named this way is because cannabis and its effects were described first, then the receptors were found later this is similar to opium and the opiate receptors, and nicotine and the nicotinic receptors.
The endocannabinoid system is present without you ever being exposed to cannabis, or any extrinsic cannabis-related compounds. Your body, on its own, will produce substances which act on and change these systems in some way, whether short-term or long lasting.
Both of these compounds were only discovered within the last two decades and Endocannabinoids can be produced in a couple of different ways some we know more about than others , but in general, we know a couple important points about their production: Endocannabinoids are also broken down very quickly to a variety of different products.
In fact, AEA is quite unstable, which makes it quite difficult to study. Many of these breakdown products are also active and produce a variety of responses on their own. For example, both 2-AG and AEA can break down to arachidonic acid, which can then be further broken down to a variety of different substances called prostaglandins, some of which can be anti-inflammatory.
An Overview of the Endocannabinoid System
The neurophysiology of acute pain due to a brief single noxious event is . The endogenous cannabinoid system has been described as “an ancient and is involved in the etiology of certain human lifestyle diseases, such. 60 Second Summary By stimulating the endocannabinoid system, CBD promotes homeostasis, reduces pain sensation and decreases inflammation. . human body, suggest that it may be useful in treating a multitude of medical conditions. Knowledge of the endocannabinoid system is relatively new and lacks depth. important in preventing, managing, or even treating certain chronic conditions. In this review, we examine the individual contribution of endocannabinoids and.