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GPR55: A new member of the cannabinoid receptor clan?
British Journal of Pharmacology
Abstract
In this issue of the British Journal of Pharmacology, Ryberg et al. present convincing in vitro evidence that the orphan GPCR, GPR55, is a cannabinoid receptor. GPR55 was activated by a range of plant, synthetic and endogenous cannabinoids and blocked by the non-psychoactive phytocannabinoid, cannabidiol. Their experiments have revealed several differences between the pharmacology of GPR55 and the established cannabinoid CB1 and CB2 receptors. For example, the CB1 receptor antagonist, AM251, activated GPR55 and the main psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol, displayed greater efficacy at GPR55 than at CB1 or CB2 receptors. They also compared the distribution of GPR55 and CB1 mRNA in mouse and report that GPR55 couples to Gα13, that it is activated by virodhamine, palmitoylethanolamide and oleoylethanolamide, and that virodhamine displays relatively high efficacy as a GPR55 agonist. Still to be identified are the main roles played by GPR55 in health and disease and any potential therapeutic benefits of activating or blocking this receptor.
British Journal of Pharmacology (2007) 152, 984–986; doi:10.1038/sj.bjp.0707464; published online 17 September 2007
... GPR55 is expressed in several mammalian tissues, such as breast adipose tissue, the testis, spleen, and several regions of the brain [13,14,16]. GPR55 was proposed to function as a cannabinoid receptor [13,14,[17][18][19][20][21]. Of note, GPR55 2 of 13 has low sequence identity with the CB1 receptor (13.5%) and the CB2 receptor (14.4%), respectively [2,3,8,13]. ...
... We subsequently identified LPI, particularly, 2-arachidonoyl LPI, as an endogenous ligand for GPR55 through the activation of extracellular signal-regulated kinase (ERK) and a rapid transient increase in intracellular free Ca 2+ ([Ca 2+ ] i ) in GPR55-expressing HEK293 cells [22][23][24]. However, even with our and other investigators' efforts, the physiological and/or pathophysiological significance of LPI- GPR55 has not yet been elucidated in as much detail as that of other lysophospholipid mediators, such as LPA and S1P [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. ...
... Since GPR55 was previously identified as another type of cannabinoid receptor [13,14,[16][17][18][19][20][21], the effects of several cannabinoid ligands were examined ( Figure 1D). 2-AG, the endogenous agonist for CB1 and CB2 receptors, did not induce the cell rounding of GPR55expressing HEK293 cells. ...
We previously reported that lysophosphatidylinositol (LPI) functions as an endogenous agonist of GPR55, a novel cannabinoid receptor. However, the physiological roles of LPI-GPR55 have not yet been elucidated in detail. In the present study, we found that LPI induced morphological changes in GPR55-expressing HEK293 cells. LPI induced the cell rounding of GPR55-expressing HEK293 cells but not of empty-vector-transfected cells. LPI also induced the activation of small GTP-binding protein RhoA and increased stress fiber formation in GPR55-expressing HEK293 cells. The inhibition of RhoA and Rho kinase ROCK by the C3 exoenzyme and the ROCK inhibitor reduced LPI-induced cell rounding and stress fiber formation. These results clearly indicated that the LPI-induced morphological changes and the assembly of the cytoskeletons were mediated through the GPR55-RhoA-ROCK pathway.
... However, quite recently, it has been demonstrated that some of the biological effects of cannabinoids are CB 1 /CB 2 receptorindependent and the existence of so-called atypical cannabinoid receptors has been discovered. Amongst them, the orphan metabotropic receptor GPR55, sometimes referred to as the CB 3 receptor, is mentioned [2]. GPR55 receptors have a low sequence homology to CB 1 (13.5%) and CB 2 (14.4%) receptors [3]. ...
... Amongst them, the orphan metabotropic receptor GPR55, sometimes referred to as the CB 3 receptor, is mentioned [2]. GPR55 receptors have a low sequence homology to CB 1 (13.5%) and CB 2 (14.4%) receptors [3]. They are modulated by several diverse non-cannabinoid (i.e., L-lipophosphatidylinostiolan endogenous lipid mediator) and cannabinoid ligands, including: endogenous cannabnoidsanandamide and 2-arachidonoylglycerol, phytocannabinoiddelta-9-tetrahydrocannabinol, synthetic cannabinoids -JWH-015, rimonabant, AM251, and atypical cannabinoid -O-1602 [2,3]. ...
... GPR55 receptors have a low sequence homology to CB 1 (13.5%) and CB 2 (14.4%) receptors [3]. They are modulated by several diverse non-cannabinoid (i.e., L-lipophosphatidylinostiolan endogenous lipid mediator) and cannabinoid ligands, including: endogenous cannabnoidsanandamide and 2-arachidonoylglycerol, phytocannabinoiddelta-9-tetrahydrocannabinol, synthetic cannabinoids -JWH-015, rimonabant, AM251, and atypical cannabinoid -O-1602 [2,3]. It has been revealed that GPR55 receptors activate G q and G α12/13 proteins and affect different signaling pathways like calcium release from the intracellular stores and the signaling dependent on Rho kinase, small GTPases (RhoA, cdc42, rac1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nuclear factor of activated T-cells (NFAT), and cAMP response element binding (CREB) [4]. ...
... [17] CB1 and CB2 receptors The cannabinoid receptors are guanidine nucleotide binding protein (G-Protein) coupled receptors, SKR6 (CB1) and CX5 (CB2). [18,19] The CB1 and CB2 receptors have been identified and cloned in the 90's. [17][18][19] This has immensely contributed to the understanding of cannabinoids. ...
... [18,19] The CB1 and CB2 receptors have been identified and cloned in the 90's. [17][18][19] This has immensely contributed to the understanding of cannabinoids. [20] CB1 receptors are preferentially distributed in basal ganglia, hippocampus, cerebellum, and cerebral cortex of the brain, whereas CB2 receptors are prominent in gut and immune tissues. ...
The use of cannabis for medical purposes has been a subject for discussion for so many years. Cannabis as a source of medical treatment first came to light in the 19th century. However, origins of cultivation of marijuana as a medical plant can be traced back to thousands of years. Attempts to completely legalize the use of cannabis for medical purposes are strongly contested in many places due to some of its negative effects on users physically, psychologically, and socially. This review is aimed to discuss the mechanism of action and pharmacogenetics of cannabinoids to elucidate its uses as medicine as well as negative effects. Online searches on the following database: Google Scholar, PubMed, Biomed Central, and SciELO were done. An attempt was made to review articles with keywords such as cannabis, cannabinoid receptors, genes, and medical marijuana. This review has highlighted with evidence the importance of genomic profiling to prevent side effects associated with predisposing genes for the benefit of patients who are medical candidates for medicinal cannabis use. Medical profiling via cannabinoid gene expression studies of patients who are medical candidates of cannabis could prevent the negative effects associated with its use.
... Some refer to GPR55 as CB3 receptor after specific binding to AEA, cannabidiol (CBD), abnormal cannabidiol (abn-CBD), virodhamine, palmitoylethanolamide and oleoylethanolamide. 24,25 GPR55 activity is coupled to Gα12/13 proteins, associated with RhoA, cdc42 and rac1 activation. Its interaction with Gαq proteins induces changes in intracellular Ca 2+ and extracellular signal-regulated kinase ERK ½ phosphorylation. ...
... 3,4,76,77 Diabetic rats treated chronically with 3 to 5 mg/day of THC presented improvement in glucose tolerance, total cholesterol, HDL and LDL, small decrease in body weight, increased total area of islets, and upregulation of gene expression for CB1 receptor, glucose transporter GLUT2, uncoupling protein UCP2, and protein kinase B. 49,78 These studies suggest THC treatment could improve hyperlipidemia, hyperglycemia, and islet dysfunction. 25,26 However, we assume that therapeutic effects of THC should be promoted as agonist of GPR55 receptor, after CB1 receptor presents oversaturation at nanomolar range. Unpublished data from our group suggest chronic exposure to THC increases insulin secretion in isolated islets, and improves oral glucose tolerance test in prediabetic mice, but decrease gene expression meanwhile islet structure remains unchanged (García-Luna and Vilches-Flores, 2023). ...
The following review focuses on the scientific studies related to the role of endocannabinoid system (ECS) in pancreatic islet physiology and dysfunction. Different natural or synthetic agonists and antagonists have been suggested as an alternative treatment for diabetes, obesity and metabolic syndrome. Therapeutic use of Cannabis led to the discovery and characterization of the ECS, a signaling complex involved in regulation of various physiological processes, including food intake and metabolism. After the development of different agonists and antagonists, evidence have demonstrated the presence and activity of cannabinoid receptors in several organs and tissues, including pancreatic islets. Insulin and glucagon expression, stimulated secretion, and the development of diabetes and other metabolic disorders have been associated with the activity and modulation of ECS in pancreatic islets. However, according to the animal model and experimental design, either endogenous or pharmacological ligands of cannabinoid receptors have guided to contradictory and paradoxical results that suggest a complex physiological interaction. In consensus, ECS activity modulates insulin and glucagon secretions according to glucose in media; over-stimulation of cannabinoid receptors affects islets negatively, leading to glucose intolerance, meanwhile the treatment with antagonists in diabetic models and humans suggests an improvement in islets function.
... The most well described targets for cannabinoids are their specific receptors, the cannabinoid receptors CB 1 and CB 2 [14,15], but their pharmacological actions are not solely limited to these receptors. Indeed, cannabinoids are lipophilic and certain cannabinoids have also been shown to target a wide range of receptors, including the peroxisome proliferator-activated receptors (PPARs), the transient receptor potential cation channel subfamily V member 1 (TRPV1), G proteincoupled receptor 55 (GPR55), the 5-hydroxytryptamine receptor subtype 1A (5-HT1A), glycine 1 and 1 receptors, in addition to ion channels (Ca 2+ ) and enzymes such as the adenosine membrane transporter phospholipase A2, lipoxygenase (LO) and cyclooxygenase-2 (COX-2) [16][17][18][19][20][21][22]. Depending both on the cannabinoid structure and cell/tissue targeted, the pharmacological effects of cannabinoids may vary. ...
... Although CB 1 and CB 2 are considered classic cannabinoid receptors, much evidence suggests the existence of further receptor targets for cannabinoids, including nuclear PPARs, GPR55 and the TRPV1. Although GPR55 shares a low amino acid sequence homology with both CB 1 and CB 2 , data indicate that GPR55 is a receptor for cannabinoid ligands including AEA, PEA, THC and CBD [16,17,[131][132][133][134][135]. TRPV1 is a cationic channel receptor dependent on intrinsic and extrinsic calcium concentrations, and evidence indicates that TRPV1 is a target for CBD, 2-AG and AEA [18,136,137]. ...
Cannabidiol (CBD), one of the primary non-euphoric components in the Cannabis sativa L. plant, has undergone clinical development over the last number of years as a therapeutic for patients with Lennox-Gastaut syndrome and Dravet syndromes. This phytocannabinoid demonstrates functional and pharmacological diversity, and research data indicate that CBD is a comparable antioxidant to common antioxidants. This review gathers the latest knowledge regarding the impact of CBD on oxidative signalling, with focus on the proclivity of CBD to regulate antioxidants and control the production of reactive oxygen species. CBD is considered an attractive therapeutic agent for neuroimmune disorders, and a body of literature indicates that CBD can regulate redox function at multiple levels, with a range of downstream effects on cells and tissues. However, pro-oxidant capacity of CBD has also been reported, and hence caution must be applied when considering CBD from a therapeutic standpoint. Such pro- and antioxidant functions of CBD may be cell- and model-dependent, and may also be influenced by CBD dose, the duration of CBD treatment and the underlying pathology.
... We note another study reporting that the microinjection of palmitoylethanolamide (PEA), an endogenous agonist for both GPR55 and PPARα [45,46], into the ventral hippocampus (vHipp), increased the firing and bursting activity of VTA DA neurons. This effect was found to be blocked by a selective GPR55 antagonist, CID 16020046 [47], suggesting a potential involvement of a DAdependent mechanism. ...
G protein-coupled receptor 55 (GPR55) has been thought to be a putative cannabinoid receptor. However, little is known about its functional role in cannabinoid action and substance use disorders. Here we report that GPR55 is predominantly found in glutamate neurons in the brain, and its activation reduces self-administration of cocaine and nicotine in rats and mice. Using RNAscope in situ hybridization, GPR55 mRNA was identified in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons, with no detection in midbrain dopamine (DA) neurons. Immunohistochemistry detected a GPR55-like signal in both wildtype and GPR55-knockout mice, suggesting non-specific staining. However, analysis using a fluorescent CB1/GPR55 ligand (T1117) in CB1-knockout mice confirmed GPR55 binding in glutamate neurons, not in midbrain DA neurons. Systemic administration of the GPR55 agonist O-1602 didnt impact ∆⁹-THC-induced analgesia, hypothermia and catalepsy, but significantly mitigated cocaine-enhanced brain-stimulation reward caused by optogenetic activation of midbrain DA neurons. O-1602 alone failed to alter extracellar DA, but elevated extracellular glutamate, in the nucleus accumbens. In addition, O-1602 also demonstrated inhibitory effects on cocaine or nicotine self-administration under low fixed-ratio and/or progressive-ratio reinforcement schedules in rats and wildtype mice, with no such effects observed in GPR55-knockout mice. Together, these findings suggest that GPR55 activation may functionally modulate drug-taking and drug-seeking behavior possibly via a glutamate-dependent mechanism, and therefore, GPR55 deserves further study as a new therapeutic target for treating substance use disorders.
... Regarding the effects of CBD in epilepsy, it is not yet clear how it exerts its action (a summary of this mechanism was shown in figure 2). However, it has been proposed that the anticonvulsant action of CBD is exerted through several mechanisms independently of CB1 receptors [114], instead including the effects on 5-HT 1A receptors, vanilloid TRPV1 receptors, N-metil D-Aspartat receptors (NMDA), GPR55 receptors, Ca ++ flux regulation, increased adenosine signaling, and interaction with GABAergic receptors [36,101,103,[115][116][117][118][119][120][121][122]. In addition to the anticonvulsant potential of CBD [103,123], a neuroprotective effect has been proposed, restoring hippocampal interneuron functions in a temporal lobe epilepsy model [124][125][126]. ...
Neurodegenerative diseases have complex etiologies, however, neuroinflammation and oxidative stress are important markers in this pathogenesis and, in this sense, cannabinoids, especially CBD, have been identified as potential therapeutics for playing a neuroprotective role. Studies have demonstrated the neuroprotective effect of cannabinoids and derivatives of Cannabis sativa L in diseases of the central nervous system due to their interaction with the endocannabinoid system through receptors and other molecular targets. The aim of this review was to provide an overview of the endocannabinoid system and a summary of the clinical and preclinical findings of the therapeutic use of cannabinoids in epilepsy, multiple sclerosis and Parkinson’s disease, pointing out interactions with molecular targets and the potential for neuroprotection of CBD. Electronic searches were carried out in international databases, including studies that presented consistent data on this subject. Significant therapeutic effects of CBD were shown for epilepsy and Parkinson’s disease, while nabiximols contributed to the reduction of spasticity, being a frequent option for the treatment of multiple sclerosis. Although much has been projected on the therapeutic potential of cannabinoids for neurological disorders, there is a long way to go in the search for strong scientific evidence of their pharmacological effectiveness.
... We note another report that intra-ventral hippocampus (intra-vHipp) microinjection of PEA, an endogenous GPR55 and PPARa agonist 44,45 increased ring and bursting activity of VTA DA neurons, an effect that was blocked by a selective GPR55 antagonist CID16020046 46 , suggesting that a DAdependent mechanism may underlie GPR55 action. However, in the present study, we did not detect GPR55 expression in VTA DA neurons. ...
Cannabis legalization continues to progress in the USA for medical and recreational purposes. G protein-coupled receptor 55 (GPR55) is a putative “CB3” receptor. However, its functional role in cannabinoid action and drug abuse is not explored. Here we report that GPR55 is mainly expressed in cortical and subcortical glutamate neurons and its activation attenuates nicotine taking and seeking in rats and mice. RNAscope in situ hybridization detected GPR55 mRNA in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons in wildtype, but not GPR55-knockout, mice. GPR55 mRNA was not detected in midbrain dopamine (DA) neurons in either genotype. Immunohistochemistry assays detected GPR55-like staining, but the signal is not GPR55-specific as the immunostaining was still detectable in GPR55-knockout mice. We then used a fluorescent CB1-GPR55 ligand (T1117) and detected GPR55 binding in cortical and subcortical glutamate neurons, but not in midbrain DA neurons, in CB1-knockout mice. Systemic administration of O-1602, a GPR55 agonist, dose-dependently increased extracellular glutamate, not DA, in the nucleus accumbens. Pretreatment with O-1602 failed to alter Δ ⁹ -tetrahydrocannabinol (D ⁹ -THC)-induced triad effects or intravenous cocaine self-administration, but it dose-dependently inhibited nicotine self-administration under fixed-ratio and progressive-ratio reinforcement schedules in rats and wildtype mice, not in GPR55-knockout mice. O-1602 itself is not rewarding or aversive as assessed by optical intracranial self-stimulation (oICSS) in DAT-Cre mice. These findings suggest that GPR55 is functionally involved in nicotine reward process possibly by a glutamate-dependent mechanism, and therefore, GPR55 deserves further research as a new therapeutic target for treating nicotine use disorder.
... We examined RNA expression in order to characterize our relevant cell lines in terms of gene expression of cannabinoid receptors [22], as well as receptors known to mediate cannabinoid signaling [23,24]. A high expression of CNR1 (CB 1 ), TRPV1, and TRPV2 was noted. ...
Simple Summary
The survival rate of head and neck cancer has only improved slightly over the last quarter century, raising the need for novel therapies to better treat this disease. This research examined the anti-tumor effects of 24 different types of cannabis extracts on head and neck cancer cells. Type III decarboxylated extracts with high levels of Cannabidiol (CBD) were the most effective in killing cancer cells. From these extracts, the specific active molecules were recognized. Combining CBD with Cannabichromene (CBC) in a 2:1 ratio made the effect even stronger. These findings can help doctors match cannabis extracts to treat head and neck cancer. CBD extracts enriched with the non-psychoactive CBC can offer patients more effective treatment. Further research is needed to develop new topical treatments from such extracts.
Abstract
Cannabis sativa plants have a wide diversity in their metabolite composition among their different chemovars, facilitating diverse anti-tumoral effects on cancer cells. This research examined the anti-tumoral effects of 24 cannabis extracts representative of three primary types of chemovars on head and neck squamous cell carcinoma (HNSCC). The chemical composition of the extracts was determined using High-Performance Liquid Chromatography (HPLC) and Mass Spectrometry (MS). The most potent anti-tumoral extracts were type III decarboxylated extracts, with high levels of Cannabidiol (CBD). We identified extract 296 (CAN296) as the most potent in inducing HNSCC cell death via proapoptotic and anti-proliferative effects. Using chemical fractionation of CAN296, we identified the CBD fraction as the primary inducer of the anti-tumoral activity. We succeeded in defining the combination of CBD with cannabichromene (CBC) or tetrahydrocannabinol (THC) present in minute concentrations in the extract, yielding a synergic impact that mimics the extract’s full effect. The cytotoxic effect could be maximized by combining CBD with either CBC or THC in a ratio of 2:1. This research suggests using decarboxylated CBD-type extracts enriched with CBC for future preclinical trials aimed at HNSCC treatment.
... Another GPCR, the GPR55, was found to be activated by THC, CBD and 2-AG, with THC and 2-AG possessing higher agonistic efficacy and potency, respectively, for this receptor over CB1R and CB2R. Thus, the GPR55 has been proposed to in fact be the third cannabinoid receptor [42]. Minor cannabinoids such as cannabigerol (CBG) and cannabichromene (CBC) have been demonstrated to exert analgesic effects through affecting other targets than the cannabinoid receptors (e.g., inhibition of AEA re-uptake, inhibition of certain serotonin receptors, inhibition of enzymes involved in synthesis of inflammatory mediators and activation of certain adrenergic receptors) [30]. ...
The analgesic potential of Cannabis sativa L.—based medicinal cannabis products for treatment of cancer associated chronic pains has gained increased interest in recent years. To ensure a controlled distribution of these products and investigate their therapeutic potential, several countries have established so-called pilot trials. Many doctors, however, are hesitant to prescribe medicinal cannabis primarily due to lack of research evidence regarding the products’ efficacy, safety and thus questionable dosing guidelines. This review aims to elucidate clinical research supporting administration of medicinal cannabis in cancer patients for analgesic purposes. The cannabinoids’ effects on the endocannabinoid system (ECS) and its implication in pain regulation is included to illustrate the complexity related to this research field. Published clinical studies on medicinal cannabis primarily consist of observational studies and only one pilot randomized controlled trial (RCT), where more RCTs exist on the cannabis-based product, Sativex® (GW Pharma Ltd., Cambridge, UK). The studies indicate analgesic potential, however non-significantly, for most patients and with acceptable safety profile. Summarizing, high-quality RCTs are scarce in this research field, and the limitations of the observational studies complicates interpretation of clinical outcomes. Despite discrepancy among the studies, they do show indications for administration and dosing regimens providing analgesic effects for some cancer patients.
... An overall neuroprotective effect and an improvement in motor function were seen in a mouse model treated with CB and a GPR55 agonist. This could be a primary objective of PD therapy (Pertwee 2007;Martínez-Pinilla et al. 2020;Celorrio et al. 2017). ...
Parkinson's disease is a neurodegenerative disorder which is characterised mostly by loss of dopaminergic nerve cells throughout the nigral area mainly as a consequence of oxidative stress. Muscle stiffness, disorganised bodily responses, disturbed sleep, weariness, amnesia, and voice impairment are all symptoms of dopaminergic neuron degeneration and existing symptomatic treatments are important to arrest additional neuronal death. Some cannabinoids have recently been demonstrated as robust antioxidants that might protect the nerve cells from degeneration even when cannabinoid receptors are not triggered. Cannabinoids are likely to have property to slow or presumably cease the steady deterioration of the brain's dopaminergic systems, a condition for which there is now no treatment. The use of cannabinoids in combination with currently available drugs has the potential to introduce a radically new paradigm for treatment of Parkinson's disease, making it immensely useful in the treatment of such a debilitating illness.
... While CBD has minimal activity at the CB1R orthosteric binding site (Bisogno et al., 2001;Jones et al., 2010;Pertwee, 2007;Thomas et al., 1998), it has been proposed to act as a CB1R negative allosteric modulator (Laprairie et al., 2015;Straiker et al., 2018). ...
Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsy, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3 to CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAAR gamma 2 and gephyrin puncta. Effects of LPI at both excitatory and inhibitory synapses were eliminated by CBD pretreatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated levels of GPR55 and LPI, and chronic lithium pilocarpine-induced epileptogenesis potentiated the pro-excitatory effects of LPI. We propose that CBD exerts potential therapeutic effect both by blocking synaptic effects of LPI and dampening hyperexcitability.
... Additionally, PEA can directly activate the G protein-coupled receptor 55 (GPR55) [25] and G protein-coupled receptor 119 (GPR119) [11]. Furthermore, it has been proposed that PEA indirectly potentiates the CB1 signal by inhibiting the degradation of AEA, a phenomenon known as the "entourage effect" [26,27]. ...
Palmitoylethanolamide (PEA), the naturally occurring amide of ethanolamine and palmitic acid, is an endogenous lipid compound endowed with a plethora of pharmacological functions, including analgesic, neuroprotective, immune-modulating, and anti-inflammatory effects. Although the properties of PEA were first characterized nearly 65 years ago, the identity of the receptor mediating these actions has long remained elusive, causing a period of research stasis. In the last two decades, a renewal of interest in PEA occurred, and a series of interesting studies have demonstrated the pharmacological properties of PEA and clarified its mechanisms of action. Recent findings showed the ability of formulations containing PEA in promoting oligodendrocyte differentiation, which represents the first step for the proper formation of myelin. This evidence opens new and promising research opportunities. White matter defects have been detected in a vast and heterogeneous group of diseases, including age-related neurodegenerative disorders. Here, we summarize the history and pharmacology of PEA and discuss its therapeutic potential in restoring white matter defects.
... GPR55 also belongs to the family of GPCRs and has been reported to be activated by low concentrations of AN and 2-AG [205,206]. Furthermore, GPR55 and CB1 receptors have been shown to be able to form heteromers [207,208]. As with TRPV1, it has been suggested that activation of GPR55 plays an opposite role to CB1 receptors, inducing neurotransmitter release [209]. ...
Adequate homeostasis of lipid, protein and carbohydrate metabolism is essential for cells to perform highly specific tasks in our organism, and the brain, with its uniquely high energetic requirements, poses singular characteristics. Some of these are related to its extraordinary dotation of synapses, the specialized subcelluar structures where signal transmission between neurons occurs in the central nervous system. The post-synaptic compartment of excitatory synapses, the dendritic spine, harbors key molecules involved in neurotransmission tightly packed within a minute volume of a few femtoliters. The spine is further compartmentalized into nanodomains that facilitate the execution of temporo-spatially separate functions in the synapse. Lipids play important roles in this structural and functional compartmentalization and in mechanisms that impact on synaptic transmission. This review analyzes the structural and dynamic processes involving lipids at the synapse, highlighting the importance of their homeostatic balance for the physiology of this complex and highly specialized structure, and underscoring the pathologies associated with disbalances of lipid metabolism, particularly in the perinatal and late adulthood periods of life. Although small variations of the lipid profile in the brain take place throughout the adult lifespan, the pathophysiological consequences are clinically manifested mostly during late adulthood. Disturbances in lipid homeostasis in the perinatal period leads to alterations during nervous system development, while in late adulthood they favor the occurrence of neurodegenerative diseases.
... CB2 receptors, responsible for the anti-inflammatory effect of cannabinoids, are located majorly in immune cells [1,6], but also within astrocytes and microglia, where they are involved in the modulation of the immune response, cell migration and cytokine release [5]. What is more, cannabinoids interact with some non-cannabinoid receptors, including vanilloid receptor 1 (TRPV1) [7], transient receptor potential ankyrin 1 (TRPA1) [8], G55 proteincoupled receptor (GPR55) [9] and peroxisome proliferator-activated receptors (PPARα, PPARγ) [4,10]. The diversity of cannabinoids' mechanisms of action might partially explain their pharmacological effects in very different clinical situations. ...
Cannabinoids can be successfully used in the treatment of many symptoms and diseases; however, most often they are not the drugs of first choice. They can be added to the primary therapy, which can improve its effectiveness, or be introduced as the basic treatment when the conventional methods have failed. Small clinical trials and case reports prove the benefits of applying medicinal cannabis in various indications; however, clinical trials in larger groups of patients are scarce and often controversial. Due to limited scientific evidence, it is essential to conduct further experimental trials. Understanding the role of endocannabinoids, as well as the composition of cannabis containing both phytocannabinoids and terpenes plays an important role in their clinical use. The clinical effects of cannabinoids depend, among other things, on the activity of the endocannabinoid system, the proportion of phytocannabinoids, such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), and the dosage used. The article discusses the role of phytocannabinoids and the potential of using them in different clinical cases in patients suffering from chronic pain, opioid dependence, depression and migraine, who did not respond to the conventional therapeutic methods. In each of the presented cases, the implementation of cannabinoids altered the course of the disease and resulted in symptom relief. Every decision to introduce cannabinoids to the treatment should be made individually with careful attention paid to details. Additionally, it is worth taking care of good clinical communication and education so that the implemented therapy is safe, effective and properly perceived by the patient.
... We can be seen the effect of GPR55 antagonists CBD (Pertwee, 2007) and CID16020046 (Brown et al., 2018) Then, we evaluated if the stimulation of nigral [ 3 H]-GABA release by GPR55 occurs in striato-nigral terminals. First, we tested the specificity of the GPR55 antibody. ...
Striatal medium‐sized spiny neurons express mRNA and protein of GPR55 receptors that stimulate neurotransmitter release; thus, GPR55 could be sent to nigral striatal projections, where it might modulate GABA release and motor behavior. Here we study the presence of GPR55 receptors at striato‐nigral terminals, their modulation of GABA release, their signaling pathway, and their effect on motor activity. By double immunohistochemistry, we found the colocation of GPR55 protein and substance P in the dorsal striatum. In slices of the rat substantia nigra, the GPR55 agonists LPI and O‐1602 stimulated [3H]‐GABA release induced by high K+ depolarization in a dose‐dependent manner. The antagonists CID16020046 and cannabidiol prevented agonist stimulation in a dose‐dependent way. The effect of GPR55 on nigral [3H]‐GABA release was prevented by lesion of the striatum with kainic acid, which was accompanied by a decrement of GPR55 protein in nigral synaptosomes, indicating the presynaptic location of receptors. The depletion of internal Ca2+ stores with thapsigargin did not prevent the effect of LPI on [3H]‐GABA release, but the remotion or chelation of external calcium did. Blockade of Gi, Gs, PLC, PKC, or dopamine D1 receptor signaling proteins did not prevent the effect of GPR55 on release. However, the activation of GPR55 stimulated [3H]‐cAMP accumulation and PKA activity. Intranigral unilateral injection of LPI induces contralateral turning. This turning was prevented by CID16020046, cannabidiol, and bicuculline but not by SCH 23390. Our data indicate that presynaptic GPR55 receptors stimulate [3H]‐GABA release at striato‐nigral terminals through [3H]‐cAMP production and stimulate motor behavior. This article is protected by copyright. All rights reserved
... 10) Similar findings were reported by other groups. 1,3,[11][12][13] We herein investigated its expression and localization in mouse tissues and compared to the distribution in humans. for 20 min. ...
GPR55 is a G protein-coupled receptor that is proposed as a novel type of cannabinoid receptor. Lysophosphatidylinositol is an endogenous ligand for GPR55. The physiological roles of GPR55 have not yet been elucidated in detail. In the present study, the expression of Gpr55 mRNA was evaluated in various mouse tissues and organs using real-time RT-PCR. Gpr55 mRNA expression was highest in testis, the male reproductive system, among mouse tissues. Gpr55 mRNA expression was high in immune organs such as the spleen, lymph nodes, and thymus. Gpr55 mRNA was also detected in the small and large intestines. The expression of Gpr55 mRNA was relatively low in a mouse brain. The distribution of Gpr55 in mice is very similar to that in humans, however, the rank order was somewhat different. The sub-fractionation revealed that Gpr55 mRNA was expressed in both germinal cells and somatic cells in the testis. In the small intestine, Gpr55 was expressed in the duodenum, jejunum, and ileum. Gpr55 was highly expressed in B and T lymphocytes and dendritic cells in the mouse spleen.
... AM251 and 6-iodopravadoline (AM-630) are two synthetic cannabinoid CB2R inverse agonists. However, AM251 is also reported to activate GPR55 [125]. CID16020046 is a selective GPR55 antagonist recently used in the anti-cancer research. ...
The tumour microenvironment (TME) is now recognised as a hallmark of cancer, since tumour:stroma crosstalk supports the key steps of tumour growth and progression. The dynamic co-evolution of the tumour and stromal compartments may alter the surrounding microenvironment, including the composition in metabolites and signalling mediators. A growing number of evidence reports the involvement of the endocannabinoid system (ECS) in cancer. ECS is composed by a complex network of ligands, receptors, and enzymes, which act in synergy and contribute to several physiological but also pathological processes. Several in vitro and in vivo evidence show that ECS deregulation in cancer cells affects proliferation, migration, invasion, apoptosis, and metastatic potential. Although it is still an evolving research, recent experimental evidence also suggests that ECS can modulate the functional behaviour of several components of the TME, above all the immune cells, endothelial cells and stromal components. However, the role of ECS in the tumour:stroma interplay remains unclear and research in this area is particularly intriguing. This review aims to shed light on the latest relevant findings of the tumour response to ECS modulation, encouraging a more in-depth analysis in this field. Novel discoveries could be promising for novel anti-tumour approaches, targeting the microenvironmental components and the supportive tumour:stroma crosstalk, thereby hindering tumour development.
... All these data concur to demonstrate the key role of PPAR-α in controlling neuroprotective and anti-inflammatory pathways [232]. Moreover, studies showed that the protective effects exerted by PEA also include the activation of GPR55 [233] and TRPV1 [234]. Figure 6 summarizes the proposed mechanisms of action of PEA. ...
Canine and feline cognitive dysfunction syndrome is a common neurodegenerative disorder of old age and a natural model of human Alzheimer’s disease. With the unavoidable expanding life expectancy, an increasing number of small animals will be affected. Although there is no cure, early detection and intervention are vitally important to delay cognitive decline. Knowledge of cellular and molecular mechanisms underlying disease onset and progression is an equally decisive factor for developing effective approaches. Uncontrolled neuroinflammation, orchestrated in the central nervous system mainly by astrocytes, microglia, and resident mast cells, is currently acknowledged as a hallmark of neurodegeneration. This has prompted scientists to find a way to rebalance the altered crosstalk between these cells. In this context, great emphasis has been given to the role played by the expanded endocannabinoid system, i.e., endocannabinoidome, because of its prominent role in physiological and pathological neuroinflammation. Within the endocannabinoidome, great attention has been paid to palmitoylethanolamide due to its safe and pro-homeostatic effects. The availability of new ultramicronized formulations highly improved the oral bioavailability of palmitoylethanolamide, paving the way to its dietary use. Ultramicronized palmitoylethanolamide has been repeatedly tested in animal models of age-related neurodegeneration with promising results. Data accumulated so far suggest that supplementation with ultramicronized palmitoylethanolamide helps to accomplish successful brain aging.
... The G-protein coupled receptor GPR55 is a class A orphan receptor whose endogenous ligand is postulated to be lysophosphatidylinositol (LysoPI/LPI; GPR55 is also termed LPI receptor type 1, LPI1 (Kihara et al., 2014)), and some evidence suggests that this receptor may be sensitive to cannabinoids as well. GPR55 may respond to CP55,940 (a potent CB1 agonist which is fully antagonized by rimonabant (Rinaldi-Carmona et al., 1996)) as well as other cannabinoids (Ryberg et al., 2007;Kapur et al., 2009;Lauckner et al., 2008;Sharir and Abood, 2010;Pertwee, 2007). Ryberg (Ryberg et al., 2007) and Lauckner (Lauckner et al., 2008) also demonstrated differing response profiles to various cannabinoids in terms of the stimulation of GTPγS binding versus the release of intracellular calcium via GPR55. ...
The first aim of the present review is to provide an in-depth description of the cannabinoids and their known effects at various neuronal receptors. It reveals that cannabinoids are highly diverse, and recent work has highlighted that their effects on the central nervous system (CNS) are surprisingly more complex than previously recognized. Cannabinoid-sensitive receptors are widely distributed throughout the CNS where they act as primary modulators of neurotransmission. Secondly, we examine the role of cannabinoid receptors at key brain sites in the control of fear and anxiety. While our understanding of how cannabinoids specifically modulate these networks is mired by their complex interactions and diversity, a plausible framework(s) for their effects is proposed. Finally, we highlight some important knowledge gaps in our understanding of the mechanism(s) responsible for their effects on fear and anxiety in animal models and their use as therapeutic targets in humans. This is particularly important for our understanding of the phytocannabinoids used as novel clinical interventions.
... In addition to being a mixed antagonist/inverse agonist of CB1Rs, AM 251 is also an agonist of non-cannabinoid receptors, including the orphan receptor GPR 55 (Pertwee, 2007;Kapur et al., 2009). Therefore, to further assess whether the potentiation of eEPSCs is mediated by blockade of CB1Rs, we tested the effects of a neutral and selective CB1R antagonist NESS 0327 on the amplitude of eEPSCs. ...
Endocannabinoids (eCBs), which include 2-arachidonoylglycerol (2-AG) and anandamide (AEA) are lipid signaling molecules involved in the regulation of an array of behavioral and physiological functions. Released by postsynaptic neurons, eCBs mediate both phasic and tonic signaling at central synapses. While the roles of phasic eCB signaling in modulating synaptic functions and plasticity are well characterized, very little is known regarding the physiological roles and mechanisms regulating tonic eCB signaling at central synapses. In this study, we show that both 2-AG and AEA are constitutively released in the dorsal raphe nucleus (DRN), where they exert tonic control of glutamatergic synaptic transmission onto serotonin (5-HT) neurons. The magnitude of this tonic eCB signaling is tightly regulated by the overall activity of neuronal network. Thus, short term in vitro neuronal silencing or blockade of excitatory synaptic transmission abolishes tonic eCB signaling in the DRn. Importantly, in addition to controlling basal synaptic transmission, this study reveals that tonic 2-AG, but not AEA signaling, modulates synaptic plasticity. Indeed, short-term increase in tonic 2-AG signaling impairs spike-timing dependent potentiation (tLTP) of glutamate synapses. This tonic 2-AG-mediated homeostatic control of DRN glutamate synapses is not signaled by canonical cannabinoid receptors, but by intracellular peroxisome proliferator-activated receptor gamma (PPARγ). Further examination reveals that 2-AG mediated activation of PPARγ blocks tLTP by inhibiting nitric oxide (NO), soluble guanylate cyclase, and protein kinase G (NO/sGC/PKG) signaling pathway. Collectively, these results unravel novel mechanisms by which tonic 2-AG signaling integrates network activities and controls the synaptic plasticity in the brain.
... All these reports concurred to demonstrate that PEA exerted these effects through the PPARα by the use of selective antagonists, corroborated by experiments in models where the receptor was genetically ablated [291][292][293]. However, studies showed that PEA effects could involve also the orphan G-protein coupled receptor 55 [294], and the transient receptor potential vanilloid type 1 channel [295]. Moreover, PEA is able to exert an indirect activation of cannabinoid receptors, via the so-called entourage effect [296], working as a false substrate for fatty acid amide hydrolase, an enzyme involved in the metabolism of the endocannabinoid anandamide (AEA) [297]. ...
The available treatments for patients affected by Alzheimer’s disease (AD) are not curative. Numerous clinical trials have failed during the past decades. Therefore, scientists need to explore new avenues to tackle this disease. In the present review, we briefly summarize the pathological mechanisms of AD known so far, based on which different therapeutic tools have been designed. Then, we focus on a specific approach that is targeting astrocytes. Indeed, these non-neuronal brain cells respond to any insult, injury, or disease of the brain, including AD. The study of astrocytes is complicated by the fact that they exert a plethora of homeostatic functions, and their disease-induced changes could be context-, time-, and disease specific. However, this complex but fervent area of research has produced a large amount of data targeting different astrocytic functions using pharmacological approaches. Here, we review the most recent literature findings that have been published in the last five years to stimulate new hypotheses and ideas to work on, highlighting the peculiar ability of palmitoylethanolamide to modulate astrocytes according to their morpho-functional state, which ultimately suggests a possible potential disease-modifying therapeutic approach for AD.
... PEA is also able to interact with cannabinoid receptors [42,43], ATP-sensitive K+ and transient receptor potential vanilloid type-1 (TRPV1) channels [44,45], nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB) [46], G-protein-coupled receptors 55 (GPR55) [47], and PPARα [48], exerting anti-inflammatory and pain-relieving actions [19,49]. In particular, um-PEA, having a chemical structure similar to classic endocannabinoids, enhances their effects, counteracting their catabolism and increasing their concentration (entourage effect) [42,50]. ...
The Coronavirus Disease-19 (COVID-19) pandemic has caused more than 100,000,000 cases of coronavirus infection in the world in just a year, of which there were 2 million deaths. Its clinical picture is characterized by pulmonary involvement that culminates, in the most severe cases, in acute respiratory distress syndrome (ARDS). However, COVID-19 affects other organs and systems, including cardiovascular, urinary, gastrointestinal, and nervous systems. Currently, unique-drug therapy is not supported by international guidelines. In this context, it is important to resort to adjuvant therapies in combination with traditional pharmacological treatments. Among natural bioactive compounds, palmitoylethanolamide (PEA) seems to have potentially beneficial effects. In fact, the Food and Drug Administration (FDA) authorized an ongoing clinical trial with ultramicronized (um)-PEA as an add-on therapy in the treatment of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. In support of this hypothesis, in vitro and in vivo studies have highlighted the immunomodulatory, anti-inflammatory, neuroprotective and pain-relieving effects of PEA, especially in its um form. The purpose of this review is to highlight the potential use of um-PEA as an adjuvant treatment in SARS-CoV-2 infection.
Background/Objectives: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune disease. Neuropathic pain (NP), related to peripheral inflammation, is among its earliest manifestations. This preliminary open-label investigation aimed to evaluate the efficacy of ultramicronized Palmitoylethanolamide (umPEA) in the management of NP. Methods: A total of 14 patients with CIDP, already undergoing immunoglobulin (Ig) therapy, were divided into two groups: Group A received umPEA 600 mg twice daily in addition to Ig for 60 days, followed by Ig alone until the end of the observation (180 days); Group B received Ig alone for 120 days and subsequently umPEA + Ig in the last 60 days of the study. Painful symptom intensity and quality of life were assessed by the Numeric Rating Scale, Neuropathic Pain Symptoms Inventory, and Five Dimensions Health Questionnaire. The safety umPEA profile was evaluated. Results: UmPEA in addition to immunoglobulins allowed for a significant improvement over time in all NP symptoms intensity (p = 0.0007) and in patients’ quality of life (p = 0.0036). Conclusions: This study suggests umPEA as a safe and effective treatment in addition to immunoglobulins to improve NP, ameliorating the patient’s health status. These results highlight the importance of neuroinflammation modulation in the management of CIDP’s painful symptoms, drawing attention to umPEA’s potential use also in neuropathies of different etiologies.
Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system‐related receptors and other molecular targets, such as the 5‐HT 1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5‐HT 1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5‐HT 1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.
Cannabis was used to treat convulsions and other disorders since ancient times. In the last few decades, preclinical animal studies and clinical investigations have established the role of cannabidiol (CBD) in treating epilepsy and seizures and support potential therapeutic benefits for cannabinoids in other neurological and psychiatric disorders. Here, we comprehensively review the role of cannabinoids in epilepsy. We briefly review the diverse physiological processes mediating the central nervous system response to cannabinoids, including D ⁹ -THC, cannabidiol, and terpenes. Next, we characterize the anti- and proconvulsive effects of cannabinoids from animal studies of acute seizures and chronic epileptogenesis. We then review the clinical literature on using cannabinoids to treat epilepsy, including anecdotal evidence and case studies as well as the more recent randomized-controlled clinical trials that led to FDA approval of CBD for some types of epilepsy. Overall, we seek to evaluate our current understanding of cannabinoids in epilepsy and focus future research on unanswered questions.
In this review article, we embark on a thorough exploration of cannabinoids, compounds that have garnered considerable attention for their potential therapeutic applications. Initially, this article delves into the fundamental background of cannabinoids, emphasizing the role of endogenous cannabinoids in the human body and outlining their significance in studying neurodegenerative diseases and cancer. Building on this foundation, this article categorizes cannabinoids into three main types: phytocannabinoids (plant-derived cannabinoids), endocannabinoids (naturally occurring in the body), and synthetic cannabinoids (laboratory-produced cannabinoids). The intricate mechanisms through which these compounds interact with cannabinoid receptors and signaling pathways are elucidated. A comprehensive overview of cannabinoid pharmacology follows, highlighting their absorption, distribution, metabolism, and excretion, as well as their pharmacokinetic and pharmacodynamic properties. Special emphasis is placed on the role of cannabinoids in neurodegenerative diseases, showcasing their potential benefits in conditions such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis. The potential antitumor properties of cannabinoids are also investigated, exploring their potential therapeutic applications in cancer treatment and the mechanisms underlying their anticancer effects. Clinical aspects are thoroughly discussed, from the viability of cannabinoids as therapeutic agents to current clinical trials, safety considerations, and the adverse effects observed. This review culminates in a discussion of promising future research avenues and the broader implications for cannabinoid-based therapies, concluding with a reflection on the immense potential of cannabinoids in modern medicine.
GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB1 and CB2 cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [104]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated in vitro by N-arachidonoylglycine, lysophosphatidylinositol and N-oleoylethanolamide, respectively, there is a lack of evidence for activation by these lipid messengers in vivo. As such, therefore, these receptors retain their orphan status.
Introduction: Cannabidiol (CBD) is a non-psychoactive compound of cannabis. Due to the therapeutic potential of CBD, there were given drugs through oral administration to treat pain and anti-inflammatory. The bioavailability of CBD has been reported to be poor when given through oral administration because of the high first-pass effect with cytochrome P450. Transdermal delivery systems of CBD may increase bioavailability and decrease first-pass metabolism with cytochrome P450. This study aimed to evaluate the antinociceptive and anti-inflammatory activities of CBD cream in an animal model. Formalin test and Antinociceptive activity.
Materials and Methods: We examined the antinociceptive and anti-inflammatory of CBD cream in an animal model. Formalin and writhing tests were used for the antinociceptive activity, and Acute inflammatory was used carrageenan-induced edema test.
Result: In this study, we tested the efficacy of CBD topical for antinociceptive and anti-inflammatory in an animal model. For the formalin test, in the early phase, AUC values in all treatments were significantly decreased when compared with placebo cream (P<0.0001, P<0.0001, P<0.0001, respectively), which were the same results in the late phase. Moreover, mice treated with CBD and CBD+levomenthol group showed less pain than with diclofenac usage. For the acetic induce writhing response test, The results have demonstrated that diclofenac, CBD, and CBD+levomenthol cream showed an ability to reduce writhes compared with a placebo group. Carrageenan-induced edema, The 1% CBD cream could significantly decrease paw volume from 1 to 4 h compared to the placebo group. Overall, 1% CBD cream treatment may have a high efficacy in decreasing paw volume from 1 to 4 h.
Conclusion: The study demonstrated that 1% CBD cream has potential effects for analgesia and anti-inflammation. Even though the mechanism of the therapeutic effect of a new formulation of CBD has not been completely understood, the topical of 1%CBD cream may also be a good candidate for treatment for analgesic and anti-inflammatory conditions.
Endogenously produced cannabinoids as well as phytocannabinoids broadly exhibit anti-inflammatory actions. Recent emergence of cannabis for multiple medical issues combined with reports on potent immunomodulatory actions of distinct components has underscored the therapeutic potential of cannabis. While synthetic cannabinoids that are based on structural similarities to existing class of cannabinoids have been on the rise, their application in therapeutics have been limited owing to toxicity concerns. Herein, we review the current literature that details the immunomodulatory actions of cannabinoids. Further, we highlight the complexities of cannabinoid biology and examine the potential inflammatory risks associated with use of cannabis including potential for toxic interactions between distinct constituents of cannabis.
Cannabidiol (CBD) has been used for the treatment of neuronal disease. Herein CBD was mixed with sodium cholate and Technol PG, a commercially available mixture of anionic phospholipids, which allowed for effective dispersion of the CBD in water.
Increasing evidence strongly supports the key role of neuroinflammation in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Neuroinflammation may alter synaptic transmission contributing to the progression of neurodegeneration, as largely documented in animal models and in patients’ studies. In the last few years, palmitoylethanolamide (PEA), an endogenous lipid mediator, and its new composite, which is a formulation constituted of PEA and the well-recognized antioxidant flavonoid luteolin (Lut) subjected to an ultra-micronization process (co-ultraPEALut), has been identified as a potential therapeutic agent in different disorders by exerting potential beneficial effects on neurodegeneration and neuroinflammation by modulating synaptic transmission. In this review, we will show the potential therapeutic effects of PEA in animal models and in patients affected by neurodegenerative disorders.
The therapeutic benefits of the current medications for patients with psychiatric disorders contrast with a great variety of adverse effects. The endocannabinoid system (ECS) components have gained high interest as potential new targets for treating psychiatry diseases because of their neuromodulator role, which is essential to understanding the regulation of many brain functions. This article reviewed the molecular alterations in ECS occurring in different psychiatric conditions. The methods used to identify alterations in the ECS were also described. We used a translational approach. The animal models reproducing some behavioral and/or neurochemical aspects of psychiatric disorders and the molecular alterations in clinical studies in post-mortem brain tissue or peripheral tissues were analyzed. This article reviewed the most relevant ECS changes in prevalent psychiatric diseases such as mood disorders, schizophrenia, autism, attentional deficit, eating disorders (ED), and addiction. The review concludes that clinical research studies are urgently needed for two different purposes: (1) To identify alterations of the ECS components potentially useful as new biomarkers relating to a specific disease or condition, and (2) to design new therapeutic targets based on the specific alterations found to improve the pharmacological treatment in psychiatry.
At the intersection of science and medicine, government policy, and pop culture, cannabis has prompted society since the beginning of recorded history. And yet, there is comparatively little replicable data on the plant, its constituents, and their capacity to modify human physiology. Over the past decades, several findings have pointed toward the importance of the endogenous cannabinoid system in maintaining homeostasis, making it an important target for various diseases. Here, we summarize the current state of knowledge on endogenous- and plant-based cannabinoids, address the issues related to cannabinoid-based drug discovery, and incite efforts to utilize their polypharmacological profile toward tackling diseases with a complex underlying pathophysiology. By fusing modern science and technology with the empirical data that has been gathered over centuries, we propose an outlook that could help us overcome the dearth of innovation for new drugs and synchronously redefine the future of drug discovery. Simultaneously, we call attention to the startling disconnect between the scientific, regulatory, and corporate entities that is becoming increasingly evident in this booming industry.
Alterations in the expanded endocannabinoid system (eECS) and cell membrane composition have been implicated in the pathophysiology of schizophrenia spectrum disorders. We enrolled 54 antipsychotic (AP)-naïve first-episode psychosis (FEP) patients and 58 controls and applied a targeted metabolomics approach followed by multivariate data analysis to investigate the profile changes in the serum levels of endocannabinoids: 2-arachidonoylglycerol (2-AG) and anandamide, endocannabinoids-like N-acylethanolamines (NAEs: linoleoylethanolamide, oleoylethanolamide, and palmitoylethanolamide), and their dominating lipid precursor’s phosphatidylcholines. Biomolecule profiles were measured at the onset of first-episode psychosis (FEP) and 0.6 years and 5.1 years after the initiation of AP treatment. The results indicated that FEP might be characterized by elevated concentrations of NAEs and by decreased 2-AG levels. At this stage of the disease, the NAE-mediated upregulation of peroxisome proliferator-activated receptors (PPARs) manifested themselves in energy expenditure. A 5-year disease progression and AP treatment adverse effects led to a robust increase in 2-AG levels, which contributed to strengthened cannabinoid (CB1) receptor-mediated effects, which manifested in obesity. Dynamic 2-AG, NAEs, and their precursors in terms of phosphatidylcholines are relevant to the description of the metabolic shifts resulting from the altered eECS function during and after FEP.
Inflammatory bowel disease (IBD) is a general term used to describe a group of chronic inflammatory conditions of the gastrointestinal tract of unknown etiology, including two primary forms: Crohn’s disease (CD) and ulcerative colitis (UC). The endocannabinoid system (ECS) plays an important role in modulating many physiological processes including intestinal homeostasis, modulation of gastrointestinal motility, visceral sensation, or immunomodulation of inflammation in IBD. It consists of cannabinoid receptors (CB1 and CB2), transporters for cellular uptake of endocannabinoid ligands, endogenous bioactive lipids (Anandamide and 2-arachidonoylglycerol), and the enzymes responsible for their synthesis and degradation (fatty acid amide hydrolase and monoacylglycerol lipase), the manipulation of which through agonists and antagonists of the system, shows a potential therapeutic role for ECS in inflammatory bowel disease. This review summarizes the role of ECS components on intestinal inflammation, suggesting the advantages of cannabinoid-based therapies in inflammatory bowel disease.
Uncontrolled stress can lead to vascular injury, hypertension, arrhythmia, compromised immune system alteration in microbiota activity, and neurobehavioral changes, including depression. The gut microbiota has been recently developed, not only for major depressive disorders but also cardiovascular problems, as a therapeutic concern. Since then, >100 studies have studied the link between depression and cardiovascular disease (CVD), and have shown that depression is common (≈20%–35%) in patients with CVD, and seems to be indicative of negative heart effects in patients. Depressive symptoms patients have demonstrated an elevated platelet reactivity, reduced cardiac variability, and enhanced proinflammatory signals, which are all cardiovascular‐related risk factors. The pathophysiology of depression‐related CVD is nevertheless a challenge because of the heterogeneous depressive syndromes and the etiologies. The cardiovascular effects of tetrahydrocannabinol (THC) (the key psychotropic credential of cannabis) and endocannabinoids (THC endogenous equivalents which cause type 1 [CB1] and 2 [CB2] cannabinoids) have been extensively examined based on well‐documented effects of marijuana smoke on blood pressure (BP) and heart rate (HR). Therefore, the aim of the review article is to establish the relationship of abnormal cannabidiols system‐mediated cardiovascular protection in disrupted gut/brain axis associated depression to determine the translational potential of targeting abnormal cannabidiols receptors in clinical studies.
Growing cannabis efficacy, usage frequency, legal supply, and declining awareness of danger recently led to expanded United States cannabis exposure. In turn, cannabis use among elderly people over 50 has more than tripled in a decade and has contributed toward a positive association of cannabis use with pathological conditions, which include type II diabetes, metabolic syndrome, neurovascular and cardiovascular disease. Remarkably, all these outcome results are mediated by the involvement of the ATP-sensitive K+ channel. Cardiovascular compromise is a common syndrome in preterm infants that leads to incidence and death and has been distinguished by poor systemic flow or hypotension. Conditions of cardiovascular compromise include vasodysregulation and myocardial malfunction through dysfunctional β-adrenergic activity. To avoid organ hypoperfusion progressing to tissue hypoxia-ischemia, inotropic drugs are used. Many premature children, however, respond insufficiently to inotropic activity with adrenergic agonists. The clinical disturbance including myocardial dysfunction through the activation of the ATP-sensitive K+ channel is often involved and the comparative efficacy of the nonpsychotropic cannabinoid, abnormal cannabidiol (Abn-CBD) is not yet known. Therefore, our primary aim was to investigate the molecular exploration of the cannabinoid system specifically Abn-CBD in cardiovascular protection involving dysregulated KATP.
Cannabinoids modulate diverse pain targets and possess unique multimodal analgesic mechanisms of action. Cannabinoids produce analgesia by interacting with cannabinoid receptor types 1 and 2 (CB1 and CB2), as well as G protein-coupled receptor 55 (GPR55) and transient receptor potential vanilloid type 1 (TRPV1). Cannabinoids modulate multiple supraspinal, spinal, and peripheral nociception pathways. Endocannabinoids are released on demand from postsynaptic terminals and travel retrograde to stimulate cannabinoid receptors on presynaptic terminals, inhibiting the release of excitatory neurotransmitters. Cannabinoids are classified based on their origin into three categories: endocannabinoids (present endogenously in human tissues), phytocannabinoids (plant-derived), and synthetic cannabinoids (pharmaceutical). The phytocannabinoids THC and CBD are lipophilic substances that readily cross the blood-brain barrier and interact with receptors in both the central and peripheral nervous systems, exerting analgesic effects especially in hyperalgesia and inflammatory states. This book chapter will review cannabinoids’ mechanisms of action in nociception.
Endocannabinoids are bioactive substances which participate in central motor control. The globus pallidus (GP) is a major nucleus in the basal ganglia circuit, which plays an important function in movement regulation. Both cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R) are expressed in the GP suggesting GP as a main action area of endocannabinoids. To investigate the direct electrophysiological and behavioral effects of cannabinoids in GP, in vivo single unit extracellular recordings and behavioral tests were performed in rats. Administration of WIN 55,212-2 exerted three neuronal response patterns from all sampled neurons of GP, including (1) increase of the firing rate; (2) decrease of the firing rate; (3) increase and then decrease of the firing rate. Selectively blocking CB1R by AM 251 decreased the firing rate and increased the firing rate. Selectively blocking CB2R by AM 630 did not change the firing rate significantly, which suggested that endocannabinoids modulated the spontaneous firing activity of pallidal neurons mainly via CB1R. Furthermore, co-application of AM 251, but not AM 630, blocked WIN 55,212-2-induced modulation of firing activity of pallidal neurons. Finally, both haloperidol-induced postural behavioral test and elevated body swing test (EBST) showed that unilateral microinjection of WIN 55,212-2 mainly induced contralateral-biased swing and deflection behaviors. Meanwhile, AM 251 produced opposite effect. The present in vivo study revealed that cannabinoids produced complicated electrophysiological and behavioral effects in the GP, which further demonstrated that the GP is a major functional region of endocannabinoid.
Neurodegenerative disorders are a widespread cause of morbidity and mortality worldwide, characterized by neuroinflammation, oxidative stress and neuronal depletion. The broad-spectrum neuroprotective activity of the Mediterranean diet is widely documented, but it is not yet known whether its nutritional and caloric balance can induce a modulation of the endocannabinoid system. In recent decades, many studies have shown how endocannabinoid tone enhancement may be a promising new therapeutic strategy to counteract the main hallmarks of neurodegeneration. From a phylogenetic point of view, the human co-evolution between the endocannabinoid system and dietary habits could play a key role in the pro-homeostatic activity of the Mediterranean lifestyle: this adaptive balance among our ancestors has been compromised by the modern Western diet, resulting in a “clinical endocannabinoid deficiency syndrome”. This review aims to evaluate the evidence accumulated in the literature on the neuroprotective, immunomodulatory and antioxidant properties of the Mediterranean diet related to the modulation of the endocannabinoid system, suggesting new prospects for research and clinical interventions against neurodegenerative diseases in light of a nutraceutical paradigm.
Lysophosphatidic acid (LPA) and lysophosphatidylinositol bind to the G protein-coupled receptors (GPCRs) LPA and GPR55, respectively. LPA2 , a type 2 LPA receptor, and GPR55 are highly expressed in colon cancer and involved in cancer progression. However, crosstalk between the two receptors and potential effects on cellular physiology are not fully understood. Here, using BRET analysis, we found that LPA2 and GPR55 interact in live cells. In the presence of both receptors, LPA2 and/or GPR55 activation facilitated co-internalization, and activation of GPR55, uncoupled with Gαi , induced reduction of intracellular cAMP. Notably, co-activation of receptors synergistically triggered further decline in the cAMP level, promoted cell proliferation, and increased the expression of cancer progression-related genes, suggesting that physical and functional crosstalk between LPA2 and GRR55 is involved in cancer progression.
Autophagy is a lysosomal catabolic process essential to cell homeostasis and is related to the neuroprotection of the central nervous system. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid present in Cannabis sativa. Many therapeutic actions have been linked to this compound, including autophagy activation. However, the precise underlying molecular mechanisms remain unclear, and the downstream functional significance of these actions has yet to be determined. Here, we investigated CBD-evoked effects on autophagy in human neuroblastoma SH-SY5Y and murine astrocyte cell lines. We found that CBD-induced autophagy was substantially reduced in the presence of CB1, CB2 and TRPV1 receptor antagonists, AM 251, AM 630 and capsazepine, respectively. This result strongly indicates that the activation of these receptors mediates the autophagic flux. Additionally, we demonstrated that CBD activates autophagy through ERK1/2 activation and AKT suppression. Interestingly, CBD-mediated autophagy activation is dependent on the autophagy initiator ULK1, but mTORC1 independent. Thus, it is plausible that a non-canonical pathway is involved. Our findings collectively provide evidence that CBD stimulates autophagy signal transduction via crosstalk between the ERK1/2 and AKT kinases, which represent putative regulators of cell proliferation and survival. Furthermore, our study sheds light on potential therapeutic cannabinoid targets that could be developed for treating neurodegenerative disorders.
Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [191], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [148]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.Table 1: Class A orphan GPCRs with putative endogenous ligands GPR3GPR4GPR6GPR12GPR15GPR17GPR20 GPR22GPR26GPR31GPR34GPR35GPR37GPR39 GPR50GPR63GRP65GPR68GPR75GPR84GPR87 GPR88GPR132GPR149GPR161GPR183LGR4LGR5 LGR6MAS1MRGPRDMRGPRX1MRGPRX2P2RY10TAAR2 In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).
Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands
for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry
and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a
radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent
inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids.
These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2--the two cannabinoid receptors identified thus far--with Ki values of 472 +/- 55 and 1400 +/- 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of delta 9-tetrahydrocannabinol (delta 9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of delta 9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than delta 9-THC.
Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.
There are at least 2 types of cannabinoid receptor, CB(1) and CB(2), both G protein coupled. CB(1) receptors are expressed predominantly at nerve terminals and mediate inhibition of transmitter release, whereas CB(2) receptors are found mainly on immune cells, their roles including the modulation of cytokine release and of immune cell migration. Endogenous agonists for cannabinoid receptors also exist. These "endocannabinoids" are synthesized on demand and removed from their sites of action by cellular uptake and intracellular enzymic hydrolysis. Endocannabinoids and their receptors together constitute the endocannabinoid system. This review summarizes evidence that there are certain central and peripheral disorders in which increases take place in the release of endocannabinoids onto their receptors and/or in the density or coupling efficiency of these receptors and that this upregulation is protective in some disorders but can have undesirable consequences in others. It also considers therapeutic strategies by which this upregulation might be modulated to clinical advantage. These strategies include the administration of (1) a CB(1) and/or CB(2) receptor agonist or antagonist that does or does not readily cross the blood brain barrier; (2) a CB(1) and/or CB(2) receptor agonist intrathecally or directly to some other site outside the brain; (3) a partial CB(1) and/or CB(2) receptor agonist rather than a full agonist; (4) a CB(1) and/or CB(2) receptor agonist together with a noncannabinoid, for example, morphine or codeine; (5) an inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism; (6) an allosteric modulator of the CB(1) receptor; and (7) a CB(2) receptor inverse agonist.
Mammalian tissues express at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals where they mediate inhibition of transmitter release. CB2 receptors are found mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous ligands for these receptors (endocannabinoids) also exist. These are all eicosanoids; prominent examples include arachidonoylethanolamide (anandamide) and 2-arachidonoyl glycerol. These discoveries have led to the development of CB1- and CB2-selective agonists and antagonists and of bioassays for characterizing such ligands. Cannabinoid receptor antagonists include the CB1-selective SR141716A, AM251, AM281 and LY320135, and the CB2-selective SR144528 and AM630. These all behave as inverse agonists, one indication that CB1 and CB2 receptors can exist in a constitutively active state. Neutral cannabinoid receptor antagonists that seem to lack inverse agonist properties have recently also been developed. As well as acting on CB1 and CB2 receptors, there is convincing evidence that anandamide can activate transient receptor potential vanilloid type 1 (TRPV1) receptors. Certain cannabinoids also appear to have non-CB1, non-CB2, non-TRPV1 targets, for example CB2-like receptors that can mediate antinociception and "abnormal-cannabidiol" receptors that mediate vasorelaxation and promote microglial cell migration. There is evidence too for TRPV1-like receptors on glutamatergic neurons, for alpha2-adrenoceptor-like (imidazoline) receptors at sympathetic nerve terminals, for novel G protein-coupled receptors for R-(+)-WIN55212 and anandamide in the brain and spinal cord, for novel receptors for delta9-tetrahydrocannabinol and cannabinol on perivascular sensory nerves and for novel anandamide receptors in the gastro-intestinal tract. The presence of allosteric sites for cannabinoids on various ion channels and non-cannabinoid receptors has also been proposed. In addition, more information is beginning to emerge about the pharmacological actions of the non-psychoactive plant cannabinoid, cannabidiol. These recent advances in cannabinoid pharmacology are all discussed in this review.
The endocannabinoid system functions through two well characterized receptor systems, the CB1 and CB2 receptors. Work by a number of groups in recent years has provided evidence that the system is more complicated and additional receptor types should exist to explain ligand activity in a number of physiological processes.
Cells transfected with the human cDNA for GPR55 were tested for their ability to bind and to mediate GTPgammaS binding by cannabinoid ligands. Using an antibody and peptide blocking approach, the nature of the G-protein coupling was determined and further demonstrated by measuring activity of downstream signalling pathways.
We demonstrate that GPR55 binds to and is activated by the cannabinoid ligand CP55940. In addition endocannabinoids including anandamide and virodhamine activate GTPgammaS binding via GPR55 with nM potencies. Ligands such as cannabidiol and abnormal cannabidiol which exhibit no CB1 or CB2 activity and are believed to function at a novel cannabinoid receptor, also showed activity at GPR55. GPR55 couples to Galpha13 and can mediate activation of rhoA, cdc42 and rac1.
These data suggest that GPR55 is a novel cannabinoid receptor, and its ligand profile with respect to CB1 and CB2 described here will permit delineation of its physiological function(s).
Source: US2003113814A A method for identification of an agent that modulates activity of G-protein coupled receptor 55 (GPR 55), which method comprises: (i) contacting a test agent with GPR 55 or a variant thereof which is capable of coupling to a G-protein; and (ii) monitoring for GPR 55 activity in the presence of a G-protein; thereby determining whether the test agent modulates GPR 55 activity.
There is convincing evidence that mammalian tissues express at least two types of cannabinoid receptor, CB1 and CB2, and that the endogenous cannabinoid, anandamide, and certain other eicosanoid agonists for known cannabinoid receptors can also activate vanilloid (VR1) receptors. Evidence is now also emerging that in addition to these established receptors for cannabinoids, other pharmacological targets for eicosanoid and / or non-eicosanoid cannabinoids are present in neuronal or non-neuronal tissues that include brain, spinal cord, microglial cells, heart, certain arteries, small intestine, vas deferens and peritoneum. Among new receptors to have been proposed for cannabinoids are CB2-like receptors in mouse paw and peritoneum, receptors for abnormal-cannabidiol in microglial cells and in arterial endothelial and non-endothelial cells, Gprotein coupled receptors for R-(+)-WIN55212 and anandamide in brain and spinal cord, receptors for 9- tetrahydrocannabinol and cannabinol on perivascular sensory nerves, 2-adrenoceptor-like (imidazoline) receptors at sympathetic nerve terminals and VR1-like receptors on glutamatergic neurons in hippocampus and dentate gyrus. The presence of novel allosteric sites for cannabinoids on delayed rectifier potassium channels and on 5-HT3, muscarinic M1 and M4, and glutamate GLUA1 and GLUA3 receptors has also been proposed. Current evidence for the existence of these new molecular targets for cannabinoids is summarized in this review. This evidence is largely pharmacological in nature, much of it coming from functional or binding assays with established or novel ligands, sometimes performed using tissues or cell lines that do not express CB1 or CB2 receptors. None of the proposed new cannabinoid receptors have yet been cloned.
Mammalian tissues express at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals where they mediate inhibition of transmitter release. CB2 receptors
In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2—the two cannabinoid receptors identified thus far—with Ki values of 472 ± 55 and 1400 ± 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of Δ9-tetrahydrocannabinol (Δ9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of Δ9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than Δ9-THC.
The effects of anadamide, 2-arachidonoylglycerol and related compounds on the specific binding of a radiolabeled cannabinoid receptor ligand,[3H]CP55940, to synaptosomal membranes were examined. Anandamide, an endogenous cannabinoid receptor ligand, reduced the specific binding of [3H]CP55940 to synaptosomal membranes in a dose-dependent manner: the Ki value was 89 nM. 2-Arachidonoylglycerol was also shown to bind appreciably to the cannabinoid receptor in competitive inhibition experiments. The apparent binding affinity was markedly increased when the binding assay was carried out in the presence of the esterase inhibitor DFP or at 0 degrees C. Free arachidonic acid and N-palmitoylethanolamine were almost inactive in terms of binding to the cannabinoid receptor in synaptosomal membranes. 2-Arachidonoylglycerol may be an endogenous cannabinoid receptor ligand in the brain.
Increasing evidence suggests that some cannabinoids mediate their effects independently of the known cannabinoid CB(1) and CB(2) receptors. Two recently published patents indicate that several cannabinoid receptor ligands also bind to the orphan G-protein-coupled receptor GPR55. This receptor is reported to be expressed in several tissues and might function in lipid or vascular biology. Thus, GPR55 might represent a new cannabinoid receptor.
Research into the pharmacology of individual cannabinoids that began in the 1940s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Also described is how this pharmacological research led to the discovery of cannabinoid CB 1 and CB 2 receptors and of endogenous ligands for these receptors, to the development of CB 1 ‐ and CB 2 ‐selective agonists and antagonists and to the realization that the endogenous cannabinoid system has significant roles in both health and disease, and that drugs which mimic, augment or block the actions of endogenously released cannabinoids must have important therapeutic applications. Some goals for future research are identified.
British Journal of Pharmacology (2006) 147 , S163–S171. doi: 10.1038/sj.bjp.0706406
A nonpsychoactive constituent of the cannabis plant, cannabidiol has been demonstrated to have low affinity for both cannabinoid CB1 and CB2 receptors. We have shown previously that cannabidiol can enhance electrically evoked contractions of the mouse vas deferens, suggestive of inverse agonism. We have also shown that cannabidiol can antagonize cannabinoid receptor agonists in this tissue with a greater potency than we would expect from its poor affinity for cannabinoid receptors. This study aimed to investigate whether these properties of cannabidiol extend to CB1 receptors expressed in mouse brain and to human CB2 receptors that have been transfected into CHO cells.
The [35S]GTPS binding assay was used to determine both the efficacy of cannabidiol and the ability of cannabidiol to antagonize cannabinoid receptor agonists (CP55940 and R-(+)-WIN55212) at the mouse CB1 and the human CB2 receptor.
This paper reports firstly that cannabidiol displays inverse agonism at the human CB2 receptor. Secondly, we demonstrate that cannabidiol is a high potency antagonist of cannabinoid receptor agonists in mouse brain and in membranes from CHO cells transfected with human CB2 receptors.
This study has provided the first evidence that cannabidiol can display CB2 receptor inverse agonism, an action that appears to be responsible for its antagonism of CP55940 at the human CB2 receptor. The ability of cannabidiol to behave as a CB2 receptor inverse agonist may contribute to its documented anti-inflammatory properties.
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