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.
Conditions the by and Endocannabinoid Summary System Cannabinoids Affected of
The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling. Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism.
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Endocannabinoids inhibit transmission at granule cell to purkinje cell synapses by modulating three types of presynaptic calcium channels. Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma-cells. Cannabinoids inhibit N-type calcium channels in neuroblastoma glioma-cells.
Presynaptic calcium channel inhibition underlies CB1 cannabinoid receptor-mediated suppression of gaba release. Cannabinoids modulate the P-type high-voltage-activated calcium currents in purkinje neurons.
Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in att20 cells transfected with rat-brain cannabinoid receptor. Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons.
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Back to the future. Desensitization of cannabinoid-mediated presynaptic inhibition of neurotransmission between rat hippocampal neurons in culture.
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Anti-inflammatory lipoxin a4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor. A cannabinoid CB1 receptor-positive allosteric modulator reduces neuropathic pain in the mouse with no psychoactive effects.
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In both the United States National Institutes of Health and the British Medical Association released reports on the potential therapeutic uses of Cannabis and cannabinoids. Fortunately, as the sciences of drug delivery and cannabinoid pharmacology have progressed in recent years, there are rapidly evolving technologies that will facilitate or enhance the medically indicated use of this pharmacological class of agents while overcoming the barriers imposed by unwanted or harmful psychoactive effects of Cannabis and smoking it as the only effective way to obtain adequate blood levels of cannabinoids.
The potential value of the cannabinoids for medicinal purposes arose from the discovery 28 and later cloning of endogenous cannabinoid receptors.
These are members of the seven transmembrane G-protein coupled receptor superfamily which comprise the binding sites for almost half of all contemporary drugs. The system is able to downregulate stress-related signals that lead to chronic inflammation and certain types of pain, but it is also involved in causing inflammation-associated symptoms, depending on the physiological context.
The CB 1 receptor has been cloned from humans. The CB 1 receptor appears to be responsible for the mood-enhancing effects of Cannabis as well as negative, dysphoria-inducing, and frank psychotomimetic effects in susceptible individuals.
CB 1 receptor distribution has been well characterized in the human brain. This widespread distribution in the brain matches well with the known pharmacodynamic effects of cannabinoids. In contrast, binding is sparse or absent from the brain stem, medulla, and thalamus. The paucity of CB 1 receptors in these areas helps explain the absence of life-threatening effects on vital physiological functions associated with extremely high doses of cannabinoids.
Besides the brain, the CB 1 receptor occurs in the testis, and presynaptically on sympathetic nerve terminals. Although CB 1 and CB 2 receptors share considerable structural similarities, their distribution and activity diverge. Among other actions, including pain modulation, CB 2 receptors are thought to serve an important role in immune function and inflammation.
CB 1 and CB 2 receptors inhibit adenylate cyclase via interactions at the G-protein complex. However, their activation and consequent inhibition of various ion channels differs. The physiologic role of anandamide continues to be actively explored, having been identified in central and peripheral tissues of man. It appears that the endocannabinoid system is intimately involved in tissue healing in the face of inflammatory conditions, correlating clinically with prevention and treatment of inflammation-mediated pain.
These effects include antinociception, hypomotility, and reduced memory. However, there appear to be distinct differences between anandamide and other cannabinoids with respect to their antinociceptive properties and other physiological effects which vary as a function of route of administration. It is not known whether anandamide acts at the same sites as phytocannabinoids to produce antinociception.
These studies suggest that anandamide is less potent and has a shorter duration of action than THC. Studies have demonstrated that antinociceptive effects of cannabinoids are mediated through mechanisms distinct from those responsible for other behavioral effects.
For instance, THC has additive analgesic efficacy with kappa opioid receptor agonists. This effect is blocked by kappa antagonism, but opioid receptor antagonism does not alter the psychoactive effects of THC.
For instance, there is mounting evidence that endogenous and exogenous cannabinoids exert some influence on opioid, 5HT 3 , and N-methyl-d-aspartate receptors. These interactions suggest a role for endocannabinoids in homeostatic pain modulation antinociception , thus their use as exogenous agents in pain management. Most recently, Thiago et al. Other studies have demonstrated the expression of functional CB 2 receptors in areas of human dorsal root ganglion DRG sensory neurons.
CB 2 receptor expression also has been demonstrated in the spinal cord as well as in other brain regions particularly relevant for nociceptive integration. These findings implicate CB 2 receptors in the analgesic effects produced by CB 2 agonists. From a clinical standpoint, this may provide an opportunity for therapeutic synergy. The role of CB 2 receptors in antinociception has been demonstrated in inflammatory and neuropathic pain models. Investigations involving carrageenan-induced inflammatory pain in rodents demonstrate that activation of CB 2 receptors by CB 2 -selective agonists suppresses neuronal activity in the dorsal horn via reduction in C-fiber activity and wind-up involving wide dynamic range WDR neurons.
It may now be concluded that cannabinoids play a role in endogenous homeostatic modulation of nociception, and that exogenous cannabinoids potentially offer some degree of analgesia in various pain states. Evidence continues to accumulate suggesting that cannabinoids can impact normal inhibitory pathways and pathophysiological processes influencing nociception in humans.
Positive therapeutic trials treating chronic painful conditions with cannabinoids. When cannabinoids lead to a reported reduction in pain, it remains unclear where the effects are triggered, or which aspect of the pain experience is most affected and under what circumstances. As well, different cannabinoids may lead to mechanistically different pain-relieving effects.
For instance, a recent study of functional brain imaging in human volunteers investigated the means by which THC may influence pain resulting from capsaicin-induced hyperalgesia. Instead, the data reveal that amygdala activity contributes to inter-individual response to cannabinoid analgesia, and suggest that dissociative effects of THC in the brain are relevant to pain relief in humans.
THC was first isolated from Cannabis by Raphael Mechoulam and colleagues in at the Hebrew University of Jerusalem, and they identified it as the major psychoactive component of Cannabis , with preferential binding at CB 1 receptors.
These have indications for treating anorexia in AIDS patients and as a therapy for intractable nausea and vomiting during cancer chemotherapy. In a wide range of oral doses, dronabinol, which is chemically identical to the THC extracted from plants, has not demonstrated significant pain relief in several naturally occurring and experimental pain conditions.
Its use has led to paradoxical increases in pain in the postoperative setting. Cannabidiol is a major constituent of Cannabis. It has virtually no psychoactivity compared against THC. Limited pharmacodynamic effects due to relatively weak receptor binding low affinity may be overcome with higher doses of agonist.
Whereas the dose-limiting factor with THC resides in the highly variable propensity among individuals to experience and tolerate negative affective, cognitive, and psychotomimetic effects, the ability of cannabidiol to behave as a CB 1 receptor inverse agonist may contribute to its documented mitigating action on THC psychotomimetic effects.
More recently it has been postulated that cannabidiol may exert its effects via inhibition of anandamide deactivation or otherwise enhancing anandamide signaling. Cannabidiol agonist activity at CB 2 receptors seems to account for its anti-inflammatory properties and both primary and secondary influences on pain.
This mitigating effect also has been attributed to the inverse agonist effect at CB 1 receptors by CBD. There are several on-going trials on its efficacy in treating MS-related pain. It is important to note that the dose-limiting factor is how much THC may be tolerated. The therapeutic role of cannabinoids in cancer treatment, in terms of effects on tumor cells and on cancer pain, is of great interest.
Correlations have been found between cannabinoid receptor levels and endocannabinoid activity and cancer severity, pain intensity, and survival. For treating refractory cancer-related pain, there is mounting evidence that cannabinoids may be a useful addition to current analgesic treatments.
However, to realize the full potential of cannabinoids suggested by preclinical data, it is likely that peripheral CB 1 or CB 2 receptors or modulation of endocannabinoids will have to be targeted to achieve analgesia without dose-limiting side effects. The entourage effect is the term used to describe enhancement of efficacy, with related improvement in overall therapeutic effectiveness, derived from combining phytocannabinoids and other plant-derived molecules.
Innovative conventional plant breeding has been yielding Cannabis chemotypes expressing high titers of each component for future study. A chemical class known as the terpenes shares a precursor molecule with phytocannabinoids; they are all flavor and fragrance components common to human diets. Terpenes are quite potent and affect animal and even human behavior when inhaled in very low concentrations.
They display unique therapeutic effects that may contribute meaningfully to the entourage effects of Cannabis -based medicinal extracts. Of particular interest are the phytocannabinoid—terpene interactions that could produce synergy with respect to treatment of pain and inflammation. Phytocannabinoid—terpene synergy increases the likelihood that an extensive pipeline of new therapeutic products is possible from this age-old plant.
The synergistic contributions of cannabidiol to Cannabis pharmacology—and specifically analgesia—have been scientifically demonstrated. Preclinical and clinical data indicate that cannabinoids administered together are more effective at ameliorating neuropathic pain than the use of a single agent. It selectively binds to the CB 2 receptor at nanomolar concentrations and acts as a full agonist. So this plant species produces at least two entirely different chemical substances able to target CB 2 receptors differentially.
Indeed, in cases of intractable or difficult-to-control pain, combination therapy with small doses of opioid and non-psychoactive cannabinoid receptor agonists may be an alternative way to circumvent the undesirable side effects of opioids yet obtain far greater analgesic efficacy than achieved with cannabinoids alone.
Cannabinoids may have another therapeutic benefit in managing chronic pain, with regard to sleep. Not only does normalized sleep improve pain relief and mood disorders associated with both poor pain control and poor sleep patterns, but there is significant risk of sleep-disordered breathing associated with central nervous system CNS drugs used to treat chronic pain.
It has been reported that cannabinoids suppress sleep-related apnea. This is an important area for further research and clinical application both in sleep and pain medicine. The phytocannabinoids have efficacy in the treatment of various chronic pain conditions with greatest promise as a therapeutic adjunct in treating peripheral and central neuropathic pain and inflammation-mediated chronic pain.
However, the smoked route of administration and the psychoactivity of THC—with associated concerns about abuse and long-term cognitive adverse effects—continue to pose serious and significant barriers to obtaining benefit from Cannabis among most patients and acceptability among health care professionals and regulatory agencies. A formidable barrier to oral bioavailability resides in the pharmacokinetics of naturally occurring and synthetic cannabinoids, but relatively slow elimination may provide clinical utility through prolonged duration of therapeutic effects once these agents gain entry into the systemic circulation.
The phytocannabinoids are metabolized rapidly in the liver, undergoing extensive hepatic first-pass metabolism. Cannabinoids are distributed throughout the body; they are highly lipid-soluble and accumulate in fatty tissue. The release of cannabinoids from fatty tissue is responsible for the prolonged terminal elimination half-life.
Putting these pharmacologic, clinical, and societal issues together, the direction for the future resides in the development of orally administered, highly bioavailable, non-psychoactive phytocannabinoid products that also take advantage of the entourage effect, to provide the millions of people living with debilitating pain a comparatively safe and effective form of relief.
National Center for Biotechnology Information , U. Rambam Maimonides Med J. Published online Oct Author information Copyright and License information Disclaimer. This is an open-access article. All its content, except where otherwise noted, is distributed under the terms of the Creative Commons Attribution License http: This article has been cited by other articles in PMC. Abstract The endocannabinoid system is involved in a host of homeostatic and physiologic functions, including modulation of pain and inflammation.
Cannabinoids, cannabinoid receptors, chronic pain, endocannabinoid system, phytocannabinoids. AM was the first blocker designed and has been extensively described. Both molecules, however, had a significant impact on the activity of the fatty acid amidohydrolase FAAH , the enzyme that degrades anandamide. AM is a recently described compound without inhibitory action at FAAH, which has been used to demonstrate the independence of anandamide transport and degradation processes.
Inhibitors of fatty acid amide hydrolase. As in the case of the cannabinoid receptors, different lines of research have led to the discovery of chemically heterogeneous FAAH inhibitors. The earlier inhibitors described consisted of reversible electrophilic carbonyl inhibitors trifluoromethyl ketones, alpha-keto esters and amides, and aldehydes or irreversible inhibitors sulfonyl fluorides and fluorophosphonates incorporated into the fatty acid structures.
Based on the structure of alpha-trifluoromethyl ketones a series of potent inhibitors were developed. Of these, alpha-keto N 4 -oxazolopyridine provides inhibitors that are 10 2 —10 3 times more potent than the corresponding trifluoromethyl ketones Boger et al.
A recent series of alpha heterocycles has been shown to possess very high potency and selectivity to reversibly inhibit FAAH activity in vivo and in vitro. The most potent of these new compounds is OL, which exhibits IC50 in the low nanomolar range Lichtman et al.
A different strategy has been selected by the group of Piomelli et al. These new classes of inhibitors are carbamate derivatives capable of directly interacting with the serine nucleophile of FAAH. However, these new inhibitors, although extremely potent, are not selective because they may potentially inactivate other serine hydrolases such as heart triacylglycerol hydrolase Lichtman et al. The ubiquitous presence of the endogenous cannabinoid system correlates with its role as a modulator of multiple physiological processes.
A comprehensive analysis of all the functions of the endocannabinoids is beyond the scope of the present review. 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.
How Does CBD Affect 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.