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.
of Conditions and by the Summary Endocannabinoid System Affected Cannabinoids
How ever , the. Endoca nnabinoids eCBs are. THC in different biological processes. Until now, the most. The cellular uptake from the ext racellular to the intra-. However , while there is wide experimental evi-. V ery recently , a partly trunca ted fatty. After re-uptake, the biological activity of eCBs. AG Dinh et al. Additiona lly, other enzymes showing. Also cyclooxygenase-2 COX-2 ,. For a comprehensive review on alternative path ways. Brown, ; Drmota et al.
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URB Anxiety, Cannabis dependence,. Hyperalgesia Bortolato et al. Christopoulou and Kiortsis, In addition, further concerns.
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ECS are nowadays considered intriguing targets for the devel-. A deeper and more detailed under-. Psychi atry 62, — Tod a y 13, — Di Marzo , V. Basic and Clinical Pharmac ology. Selective CB2 recept or agonism.
A sec ond fatty acid amide. CB 2 receptor activa-. Blood Flow Meta b. Bari M and Maccar rone M The. To mmaso, Bari and Maccarrone. Commercial License, which permits. Both GABAergic and glutamatergic systems have their release rate regulated by activation of the endocannabinoid system ECS Katona and Freund, , a major circuit-breaker at the peripheral and central levels Battista et al.
Beta-adrenergic receptor activation increases GABA uptake in adolescent mice frontal cortex: Modulation by cannabinoid receptor agonist WIN55, Activation in the neurons of the mesolim- bic system increases the desire for food. Jul Perm J. Pain management can be challenging following bariatric surgery, and patients with obesity tend to increase opioid use after undergoing surgery. This report quantifies marijuana MJ use and its relationship to pain and other surgery-related outcomes in a population from a state that has legalized MJ.
Data were collected for consecutive patients undergoing weight reduction surgeries between May 1, and July 31, Demographics, preoperative comorbidities, medications, and perioperative opioid use were analyzed.
The primary outcome evaluated was inpatient opioid pain medication use quantified using natural log morphine equivalents. Secondary outcomes included percentage of total body weight loss after three months, postoperative complications, and changes in medical comorbidities.
A total of patients, among whom 36 8. Perioperative opioid requirements were significantly higher in the MJ-user group natural log morphine equivalents of 3. MJ use did not affect percentage of day total body weight loss, development of postoperative complications, or improvement in medical comorbidities. Perioperative opioid use was significantly higher in the MJ-user group despite lower subjective pain scores.
The difference in opioid requirements suggests an interaction between MJ use and opioid tolerance or pain threshold. The percentage of total body weight loss, improvement in medical comorbidity, and incidence of postoperative complications at day follow-up were not affected by MJ use in this cohort analysis.
The primary endogenous can- nabinoid receptor ligands endogenous cannabinoids, or endocannabinoids are arachidonic acid derivatives, and they work via retrograde signaling receptor activation. The primary mediator of endocannabinoid signaling is N-arachidonoylethanolamine anandamide, or AEA , and 2-arachidonoylglycerol 2-AG is another primary endocannabinoid [71, .
Cannabis-based phyto- cannabinoids, as well as inherent endocannabinoids interact at the CB1 and CB2 receptors with variable affinities and actions . Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. Background Medicinal cannabis registries typically report pain as the most common reason for use.
It would be clinically useful to identify patterns of cannabis treatment in migraine and headache, as compared to arthritis and chronic pain, and to analyze preferred cannabis strains, biochemical profiles, and prescription medication substitutions with cannabis. Methods Via electronic survey in medicinal cannabis patients with headache, arthritis, and chronic pain, demographics and patterns of cannabis use including methods, frequency, quantity, preferred strains, cannabinoid and terpene profiles, and prescription substitutions were recorded.
Results Of patients, 21 illnesses were treated with cannabis. Pain syndromes accounted for Across all 21 illnesses, headache was a symptom treated with cannabis in Many pain patients substituted prescription medications with cannabis Conclusions Chronic pain was the most common reason for cannabis use, consistent with most registries. The majority of headache patients treating with cannabis were positive for migraine.
Prospective studies are needed, but results may provide early insight into optimizing crossbred cannabis strains, synergistic biochemical profiles, dosing, and patterns of use in the treatment of headache, migraine, and chronic pain syndromes.
Overactivity of the ECS in obesity and insulin resistant subjects is well-documented Maccarrone et al. Eating or not palatable hedonic food makes a great difference in terms of derangement of the ECS. Palatable food can be seductive and hedonic eating can become irresistible beyond hunger and negative consequences.
This is witnessed by the subtle equilibrium between eating to provide energy intake for homeostatic functions, and reward-induced overeating. In recent years, considerable efforts have been devoted to study neural circuits, and to identify potential factors responsible for the derangement of homeostatic eating toward hedonic eating and addiction-like feeding behavior. Thus, the role of midbrain dopamine is positioned at the intersection between selected hormonal signals involved in food reward information processing namely, leptin, ghrelin, and insulin , and lipid-derived neural mediators such as endocannabinoids.
The impact of high fat palatable food and dietary lipids on endocannabinoid formation is reviewed in its pathogenetic potential for the derangement of feeding homeostasis. Next, endocannabinoid signaling that regulates synaptic plasticity is discussed as a key mechanism acting both at hypothalamic and mesolimbic circuits, and affecting both dopamine function and interplay between leptin and ghrelin signaling. Thus, the lateral hypothalamus-ventral tegmental area-nucleus accumbens neural circuitry is reexamined in order to interrogate the functional interplay between ghrelin, dopamine, orexin, and endocannabinoid signaling.
We suggested a pivotal role for endocannabinoids in food reward processing within the lateral hypothalamus, and for orexin neurons to integrate endocrine signals with food reinforcement and hedonic eating. In addition, the role played by different stressors in the reinstatement of preference for palatable food and food-seeking behavior is also considered in the light of endocannabinoid production, activation of orexin receptors and disinhibition of dopamine neurons.
Finally, type-1 cannabinoid receptor-dependent inhibition of GABA-ergic release and relapse to reward-associated stimuli is linked to ghrelin and orexin signaling in the lateral hypothalamus-ventral tegmental area-nucleus accumbens network to highlight its pathological potential for food addiction-like behavior.
Phytomedicines in the Treatment of Migraine. Migraine is a disabling neurovascular disorder with few targeted, tolerable and effective treatments. Phytomedicines, or plant-based medicinal formulations, hold great promise in the identification of novel therapeutic targets in migraine. The CB1R is also abundantly expressed in the peripheral nervous system PNS as well as in the peripheral tissues in a region-specific manner [ 59 , 63 , 64 , 65 ] Figure 2.
Also, the CB1R is observed in trigeminal ganglion, dorsal root ganglion, and dermic nerve endings of primary sensory neurons, where it regulates nociception from afferent nerve fibers [ 65 , 66 , 67 ]. In the gastrointestinal GI tract, the CB1R is enriched in both the enteric nervous system and in non-neuronal cells in the intestinal mucosa, including enteroendocrine cells, immune cells, and enterocytes [ 68 ]. Through neuronal and non-neuronal routes, the CB1R modulates the mobility of GI tract, the secretion of gastric acids, fluids, neurotransmitter and hormones, as well as the permeability of the intestinal epithelium [ 68 ].
Intriguingly, hepatic CB1R also participates in the regulation of energy balance and metabolism, but in an unusual way. Normally, the expression of CB1R in the liver is very low [ 69 ]. However, under pathological conditions, the expression of CB1R in several types of hepatic cells is remarkably increased, where the CB1R actively contributes to hepatic insulin resistance, fibrosis, and lipogenesis [ 63 ].
Similarly, the CB1R is upregulated in the cardiovascular system under pathological conditions, which in turn, promotes disease progression and cardiac dysfunction [ 70 ].
Oxidative stress, inflammation and fibrosis have been observed as a result of CB1R activation in cardiomyocytes, vascular endothelial cells, and smooth muscle cells [ 70 ]. In addition to the aforementioned tissues, the expression of the CB1R has also been reported in adipose tissue, skeletal muscle, bone, skin, eye, reproductive system, and several types of cancer cells [ 63 ].
Major localization sites and associated functions of the CB1R in the human body. The majority of CB1Rs expressed in human body is found in the brain, where it is involved in various neurological activities. CB1Rs on the peripheral sites, although to a lesser extent, participates in the regulation of local tissue functions. However, besides the well-known plasma membrane localized CB1R, which is the typical distributional pattern of GPCRs, considerable observations have reported predominant intracellular localization of CB1Rs in diverse types of cells, including transfected non-neuronal cells, undifferentiated neuronal cells, and cultured hippocampal neurons [ 71 ].
Follow-up studies discovered that CB1Rs localized in intracellular compartments presumably consist of several distinct subpopulations Figure 3. One proportion of intracellular CB1Rs comes from the continuous internalization of plasma membrane-localized CB1R [ 72 ]. Aside from the constitutive and agonist-induced internalized CB1R, accumulated evidence suggests a distinct pool of intracellularly localized CB1R, with differential functionalities from their plasma membrane-localized counterparts.
Another subpopulation of CB1Rs, as suggested by several lines of evidence, is expressed in mitochondria. Previous studies have reported the effect of THC on mitochondria-associated enzymatic activity, which was attributed to the non-specific membrane disruption of lipophilic cannabinoids at that time [ 76 ].
However, recent studies have challenged this concept by demonstrating the presence of mitochondrial CB1R and its direct involvement in cellular respiration and DSI in hippocampal neurons [ 77 ].
Although there are discrepancies in the amplitude of the CB1R agonist-induced decreases in mitochondrial respiration, the existence and functionality of mitochondrial CB1Rs are undeniable [ 78 , 79 , 80 ].
These lines of evidence highlight the direct association between mitochondrial CB1R and proper functioning of mitochondria, which has been suggested to participate in many pathological conditions [ 84 , 85 ]. Therefore, the role of mitochondrial CB1R may not be limited to the previously discovered roles and is worth further exploration. Subcellular localization of the CB1R. Typically, the CB1R is located at cell surface and inhibits cyclic adenosine monophosphate cAMP formation and calcium influx upon activation.
Intracellular-localized CB1Rs do not translocate to plasma membrane. Instead, they form a subpopulation with pharmacological properties distinct from their plasma membrane-localized counterparts. CB1Rs located on lysosomes can increase intracellular calcium concentrations through the release of internal calcium stores, and increase the permeability of lysosomes.
Mitochondrial CB1Rs inhibit mitochondrial cellular respiration and cAMP production, hence regulating cellular energy metabolism. Follow-up studies revealed a predominant expression of the CB2R in immune cells and a moderate expression in other peripheral tissues, including the cardiovascular system, GI tract, liver, adipose tissue, bone, and reproductive system [ 10 ].
However, this concept has been challenged recently by several studies demonstrating the expression of the CB2R in the brain, albeit to a much lower extent in comparison to the immune system or the CB1R [ 57 ]. Although the expression of the CB2R in the CNS and PNS is comparatively limited, it is undeniable that the CB2R plays an active role in neurological activities, such as nociception, drug addiction and neuroinflammation [ 55 , 56 ].
However, the CB1R but not the CB2R has been reported to activate other G proteins in certain circumstances in a cell type- and ligand-dependent manner [ 88 ]. Moreover, the CB1R modulates the activity of several types of ion channels [ 88 , 94 ].
CB1R-modulated major signaling pathways. Depending on the ligand and subcellular environment, the outcome of CB1R-mediated signaling could be promotion of cell survival or cell death.
Arrows indicate stimulation; blunted arrows indicate inhibition. 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 , ]. Indeed, the CB1R and the endocannabinoid system are largely involved in various aspects of central neural activities and disorders, including appetite, learning and memory, anxiety, depression, schizophrenia, stroke, multiple sclerosis, neurodegeneration, epilepsy, and addiction [ 3 , 9 , , ].
The CB1R is also involved in physiological and pathological conditions in the PNS and peripheral tissues, including pain, energy metabolism, cardiovascular and reproductive functions, inflammation, glaucoma, cancer, and liver and musculoskeletal disorders [ 63 ]. The expression of CB1R remarkably fluctuates in many pathological conditions, underscoring its critical role in a wide spectrum of biological activities [ 69 ]. Interestingly, in some cases, both positive and negative alterations in CB1R expression and functionality have been reported [ 69 ].
Moreover, the administration of CB1R agonists exert biphasic effects in several conditions [ ]. On the other hand, the widespread presence of the CB1R limits the therapeutic application of CB1R ligands due to various side effects.
These facts underscore the significance of understanding and manipulating the endocannabinoid system in a condition-specific manner. CB1R has been found to inhibit GABA and glutamate release from presynaptic terminals, which confers the CB1R with the ability to modulate neurotransmission [ 60 , ].
This has been proposed as a plausible underlying mechanism of CB1R-mediated neuroprotection against excitotoxicity, a prominent pathological process of many neurological disorders, including epilepsy and neurodegenerative diseases [ 34 , , ]. To date, numerous studies have shown that the CB1R plays a neuroprotective role against excitotoxicity induced by various stimuli [ , , , ]. It has been demonstrated recently that in mouse brain, the neuroprotective effect exerted by CB1R against excitotoxicity is restricted to the CB1R population located on glutamatergic terminals [ ].
The upregulation of the CB1R and endocannabinoid system activity has been observed in the basal ganglia of experimental models of PD, which could be a mechanism to compensate the degenerated dopaminergic neurons of the substantia nigra, or a pathological process that contributes to the worsening of the disease [ ]. Interestingly, decreased endocannabinoid system activity has also been reported in PD models [ ].
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. Isolation, structure, and partial synthesis of an active constituent of hashish. Structure of a cannabinoid receptor and functional expression of the cloned cdna.
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International Journal of High Risk Behaviors and Addiction
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.