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1
Soraya, hiva, Ruohollah Seddigh, Fatemeh Hadi, and Mohammad Faramarzi. "Chemical cannabis; The New Trend of addiction in Iran." Iranian Journal of Psychiatry and Clinical Psychology 28, no. 1 (April 20, 2022): 10. http://dx.doi.org/10.32598/ijpcp.28.1.4010.1.
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Synthetic cannabinoids (SC) are a heterogeneous group of substances with a high affinity for cannabinoid receptors. Unlike Δ9-tetrahydrocannabinol (THC), synthetic cannabinoids are incredibly potent, highly productive, have more affinity for the Cannabinoid receptor type 1 (CB1), and Cannabinoid receptor type 2 (CB2), and are designed to accelerate the effects of tetrahydrocannabinol. Also, there is experimental evidence that SCs acts on non-cannabinoid receptors, such as the 5-HT2B receptor or dopaminergic receptors. (1, 2).
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Walsh, Kenneth B., and Andrea E. Holmes. "Pharmacology of Minor Cannabinoids at the Cannabinoid CB1 Receptor: Isomer- and Ligand-Dependent Antagonism by Tetrahydrocannabivarin." Receptors 1, no. 1 (August 2, 2022): 3–12. http://dx.doi.org/10.3390/receptors1010002.
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(1) Background: In addition to the major phytocannabinoids, trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), the cannabis plant (Cannabis sativa L.) synthesizes over 120 additional cannabinoids that are known as minor cannabinoids. These minor cannabinoids have been proposed to act as agonists and antagonists at numerous targets including cannabinoid type 1 (CB1) and type 2 (CB2) receptors, transient receptor potential (TRP) channels and others. The goal of the present study was to determine the agonist effects of the minor cannabinoids: cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabitriol (CBT) and cannabidivarin (CBDV) at the CB1 receptor. In addition, the CB1 receptor antagonist effects of Δ9-tetrahydrocannabivarin (Δ9-THCV) were compared with its isomer Δ8-tetrahydrocannabivarin (Δ8-THCV). (2) Methods: CB1 receptor activity was monitored by measuring cannabinoid activation of G protein-gated inward rectifier K+ (GIRK) channels in AtT20 pituitary cells using a membrane potential-sensitive fluorescent dye assay. (3) Results: When compared to the CB1 receptor full agonist WIN 55,212-2 and the partial agonist Δ9-THC, none of the minor cannabinoids caused a significant activation of Gi/GIRK channel signaling. However, Δ9-THCV and Δ8-THCV antagonized the effect of WIN 55,212-2 with half-maximal inhibitory concentrations (IC50s) of 434 nM and 757 nM, respectively. Δ9-THCV antagonism of the CB1 receptor was “ligand-dependent”; Δ9-THCV was more potent in inhibiting WIN 55,212-2 and 2-arachidonoylglycerol (2-AG) than Δ9-THC. (4) Conclusions: While none of the minor cannabinoids caused Gi/GIRK channel activation, Δ9-THCV antagonized the CB1 receptor in an isomer- and ligand-dependent manner.
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Li, Yong, and Jimok Kim. "CB2 Cannabinoid Receptor Knockout in Mice Impairs Contextual Long-Term Memory and Enhances Spatial Working Memory." Neural Plasticity 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/9817089.
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Neurocognitive effects of cannabinoids have been extensively studied with a focus on CB1 cannabinoid receptors because CB1 receptors have been considered the major cannabinoid receptor in the nervous system. However, recent discoveries of CB2 cannabinoid receptors in the brain demand accurate determination of whether and how CB2 receptors are involved in the cognitive effects of cannabinoids. CB2 cannabinoid receptors are primarily involved in immune functions, but also implicated in psychiatric disorders such as schizophrenia and depression. Here, we examined the effects of CB2 receptor knockout in mice on memory to determine the roles of CB2 receptors in modulating cognitive function. Behavioral assays revealed that hippocampus-dependent, long-term contextual fear memory was impaired whereas hippocampus-independent, cued fear memory was normal in CB2 receptor knockout mice. These mice also displayed enhanced spatial working memory when tested in a Y-maze. Motor activity and anxiety of CB2 receptor knockout mice were intact when assessed in an open field arena and an elevated zero maze. In contrast to the knockout of CB2 receptors, acute blockade of CB2 receptors by AM603 in C57BL/6J mice had no effect on memory, motor activity, or anxiety. Our results suggest that CB2 cannabinoid receptors play diverse roles in regulating memory depending on memory types and/or brain areas.
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SMALL-HOWARD, Andrea L., Lori M. N. SHIMODA, Chaker N. ADRA, and Helen TURNER. "Anti-inflammatory potential of CB1-mediated cAMP elevation in mast cells." Biochemical Journal 388, no. 2 (May 24, 2005): 465–73. http://dx.doi.org/10.1042/bj20041682.
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Cannabinoids are broadly immunosuppressive, and anti-inflammatory properties have been reported for certain marijuana constituents and endogenously produced cannabinoids. The CB2 cannabinoid receptor is an established constituent of immune system cells, and we have recently established that the CB1 cannabinoid receptor is expressed in mast cells. In the present study, we sought to define a role for CB1 in mast cells and to identify the signalling pathways that may mediate the suppressive effects of CB1 ligation on mast cell activation. Our results show that CB1 and CB2 mediate diametrically opposed effects on cAMP levels in mast cells. The observed long-term stimulation of cAMP levels by the Gαi/o-coupled CB1 is paradoxical, and our results indicate that it may be attributed to CB1-mediated transcriptional regulation of specific adenylate cyclase isoenzymes that exhibit superactivatable kinetics. Taken together, these results reveal the complexity in signalling of natively co-expressed cannabinoid receptors and suggest that some anti-inflammatory effects of CB1 ligands may be attributable to sustained cAMP elevation that, in turn, causes suppression of mast cell degranulation.
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Dobovišek, Luka, Fran Krstanović, Simona Borštnar, and Nataša Debeljak. "Cannabinoids and Hormone Receptor-Positive Breast Cancer Treatment." Cancers 12, no. 3 (February 25, 2020): 525. http://dx.doi.org/10.3390/cancers12030525.
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Breast cancer (BC) is the most common cancer in women worldwide. Approximately 70–80% of BCs express estrogen receptors (ER), which predict the response to endocrine therapy (ET), and are therefore hormone receptor-positive (HR+). Endogenous cannabinoids together with cannabinoid receptor 1 and 2 (CB1, CB2) constitute the basis of the endocannabinoid system. Interactions of cannabinoids with hypothalamic–pituitary–gonadal axis hormones are well documented, and two studies found a positive correlation between peak plasma endogenous cannabinoid anandamide with peak plasma 17β-estradiol, luteinizing hormone and follicle-stimulating hormone levels at ovulation in healthy premenopausal women. Do cannabinoids have an effect on HR+ BC? In this paper we review known and possible interactions between cannabinoids and specific HR+ BC treatments. In preclinical studies, CB1 and CB2 agonists (i.e., anandamide, THC) have been shown to inhibit the proliferation of ER positive BC cell lines. There is less evidence for antitumor cannabinoid action in HR+ BC in animal models and there are no clinical trials exploring the effects of cannabinoids on HR+ BC treatment outcomes. Two studies have shown that tamoxifen and several other selective estrogen receptor modulators (SERM) can act as inverse agonists on CB1 and CB2, an interaction with possible clinical consequences. In addition, cannabinoid action could interact with other commonly used endocrine and targeted therapies used in the treatment of HR+ BC.
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GÓMEZ DEL PULGAR, Teresa, Guillermo VELASCO, and Manuel GUZMÁN. "The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt." Biochemical Journal 347, no. 2 (April 10, 2000): 369–73. http://dx.doi.org/10.1042/bj3470369.
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Cannabinoids exert most of their effects in the central nervous system through the CB1 cannabinoid receptor. This G-protein-coupled receptor has been shown to be functionally coupled to inhibition of adenylate cyclase, modulation of ion channels and activation of extracellular-signal-regulated kinase. Using Chinese hamster ovary cells stably transfected with the CB1 receptor cDNA we show here that ∆9-tetrahydrocannabinol (THC), the major active component of marijuana, induces the activation of protein kinase B/Akt (PKB). This effect of THC was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoids CP-55940 and HU-210, and was prevented by the selective CB1 antagonist SR141716. Pertussis toxin and wortmannin blocked the CB1 receptor-evoked activation of PKB, pointing to the sequential involvement of a Gi/Go protein and phosphoinositide 3ʹ-kinase. The functionality of the cannabinoid-induced stimulation of PKB was proved by the increased phosphorylation of glycogen synthase kinase-3 serine 21 observed in cannabinoid-treated cells and its prevention by SR141716 and wortmannin. Cannabinoids activated PKB in the human astrocytoma cell line U373 MG, which expresses the CB1 receptor, but not in the human promyelocytic cell line HL-60, which expresses the CB2 receptor. Data indicate that activation of PKB may be responsible for some of the effects of cannabinoids in cells expressing the CB1 receptor.
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Bow, Eric W., and John M. Rimoldi. "The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation." Perspectives in Medicinal Chemistry 8 (January 2016): PMC.S32171. http://dx.doi.org/10.4137/pmc.s32171.
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The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (-)-Δ 9 -tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure–CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure–activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure–activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles.
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Zibolka, Juliane, Anja Wolf, Lisa Rieger, Candy Rothgänger, Anne Jörns, Beat Lutz, Andreas Zimmer, Faramarz Dehghani, and Ivonne Bazwinsky-Wutschke. "Influence of Cannabinoid Receptor Deficiency on Parameters Involved in Blood Glucose Regulation in Mice." International Journal of Molecular Sciences 21, no. 9 (April 30, 2020): 3168. http://dx.doi.org/10.3390/ijms21093168.
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Cannabinoids are known to influence hormone secretion of pancreatic islets via G protein-coupled cannabinoid receptor type 1 and 2 (CB1 and CB2). The present study was designed to further investigate the impact of cannabinoid receptors on the parameters involved in insulin secretion and blood glucose recognition. To this end, CB1 and CB2 receptor knockout mice (10–12 week old, both sexes) were characterised at basal state and compared to wild-type mice. The elimination of cannabinoid receptor signalling resulted in alterations of blood glucose concentrations, body weights and insulin levels. Changes were dependent on the deleted receptor type and on the sex. Analyses at mRNA and protein levels provided evidence for the impact of cannabinoid receptor deficiency on the glucose sensing apparatus in the pancreas. Both receptor knockout mouse lines showed decreased mRNA and protein amounts of glucose transporters Glut1 and Glut2, combined with alterations in immunostaining. In addition, pancreatic glucokinase expression was elevated and immunohistochemical labelling was modified in the pancreatic islets. Taken together, CB1 and CB2 signalling pathways seem to influence glucose sensing in β-cells by affecting glucose transporters and glucokinase. These alterations were more pronounced in CB2 knockout mice, resulting in higher blood glucose and lower plasma insulin levels.
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Černe, Katarina. "Toxicological properties of Δ9-tetrahydrocannabinol and cannabidiol." Archives of Industrial Hygiene and Toxicology 71, no. 1 (March 1, 2020): 1–11. http://dx.doi.org/10.2478/aiht-2020-71-3301.
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AbstractCannabis sativa L. contains more than 100 phytocannabinoids that can interact with cannabinoid receptors CB1 and CB2. None of the cannabinoid receptor ligands is entirely CB1- or CB2-specific. The effects of cannabinoids therefore differ not just because of different potency at cannabinoid receptors but also because they can interact with other non-CB1 and non-CB2 targets, such as TRPV1, GPR55, and GPR119. The most studied phytocannabinoid is Δ9-tetrahydrocannabinol (THC). THC is a partial agonist at both cannabinoid receptors, but its psychotomimetic effect is produced primarily via activation of the CB1 receptor, which is strongly expressed in the central nervous system, with the noteworthy exception of the brain stem. Although acute cognitive and other effects of THC are well known, the risk of irreversible neuropsychological effects of THC needs further research to elucidate the association. Unlike THC, phytocannabinoid cannabidiol (CBD) does not appear to have psychotomimetic effects but may interact with some of the effects of THC if taken concomitantly. CBD administered orally has recently undergone well-controlled clinical trials to assess its safety in the treatment of paediatric epilepsy syndromes. Their findings point to increased transaminase levels as a safety issue that calls for postmarketing surveillance for liver toxicity. The aim of this review is to summarise what is known about acute and chronic toxicological effects of both compounds and address the gaps in knowledge about the safety of exogenous cannabinoids that are still open.
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Barth, Francis, and Murielle Rinaldi-Carmona. "The Development of Cannabinoid Antagonists." Current Medicinal Chemistry 6, no. 8 (August 1999): 745–55. http://dx.doi.org/10.2174/0929867306666220401143808.
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The discovery of two distinct cannabinoid receptors (CB1 and C B 2 ) in the early 1990's has revived the research on cannabinoid antagonists. While the search for antagonists based on the structure of agonists (classical cannabinoids or aminoalkylindoles) appeared rather disappointing, the first potent cannabinoid antagonists were developed in a new chemical series: the diarylpyrazoles. Since its discovery in 1994, the selective CB1 antagonist SR 141716 has become a major pharmacological tool to elucidate the physiological role of the CB 1 cannabinoid receptor and its endogenous ligand. The selective CB2 antagonist SR 144528 is expected to play the same role for the CB2 receptors, while the recent development of cannabinoid antagonists belonging to other chemical series illustrates the interest of these compounds which are now considered as interesting therapeutic targets by many pharmaceutical companies.
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Simoneau, Isabelle I., Maged S. Hamza, Heriberto P. Mata, Erin M. Siegel, Todd W. Vanderah, Frank Porreca, Alexandros Makriyannis, and T. Philip Malan. "The Cannabinoid Agonist WIN55,212-2 Suppresses Opioid-induced Emesis in Ferrets." Anesthesiology 94, no. 5 (May 1, 2001): 882–87. http://dx.doi.org/10.1097/00000542-200105000-00029.
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Background Cannabinoid receptor agonists reverse nausea and vomiting produced by chemotherapy and radiation therapy in animals and humans but have not been tested against opioid-induced emesis. This study tests the hypothesis that cannabinoid receptor agonists will prevent opioid-induced vomiting. Methods Twelve male ferrets were used. They weighed 1.2-1.6 kg at the beginning and 1.8-2.3 kg at the end of the experiments. All drugs were injected subcutaneously. WIN55,212-2, a mixed CB1-CB2 cannabinoid receptor agonist, was administered 25 min before morphine. Retches and vomits were counted at 5-min intervals for 30 min after morphine injection. Results Retching and vomiting responses increased with increasing morphine doses up to 1.0 mg/kg, above which the responses decreased. Previous administration of naloxone prevented morphine-induced retching and vomiting. WIN55,212-2 dose-dependently reduced retching and vomiting. The ED50 was 0.05 mg/kg for retches and 0.03 mg/kg for vomits. At 0.13 mg/kg, retching decreased by 76% and vomiting by 92%. AM251, a CB1 receptor-selective antagonist, blocked the antiemetic actions of WIN55,212-2, but AM630, a CB2 receptor-selective antagonist, did not. Conclusions These results demonstrate that WIN55,212-2 prevents opioid-induced vomiting and suggest that the antiemetic activity of WIN55,212-2 occurs at CB1 receptors. This is consistent with findings that CB1 receptors are the predominant cannabinoid receptors in the central nervous system and that antiemetic effects of cannabinoids appear to be centrally mediated.
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Andrzejewska, Angelika, Klaudia Staszak, Marta Kaczmarek-Ryś, Ryszard Słomski, and Szymon Hryhorowicz. "Understanding cannabinoid receptors: structure and function." Folia Biologica et Oecologica 14 (December 30, 2018): 1–13. http://dx.doi.org/10.1515/fobio-2017-0004.
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The endocannabinoid system (ECS) consists of the endocannabinoids, cannabinoid receptors and the enzymes that synthesize and degrade endocannabinoids. The whole EC system plays an important role in the proper functioning of the central and autonomic nervous system. ECS is involved in the regulation of the body energy and in the functioning of the endocrine system. It can affect on the regulation of emotional states, motoric movement, operations of the endocrine, immune and digestive system. Many of the effects of cannabinoids are mediated by G coupled –protein receptors: CB1, CB2 and GPR55 but also of transient receptor potential channels (TRPs) which not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides. In this review work we briefly summarize the role and action of cannabinoid receptors CB1 and CB2, protein-coupled receptor 55 (GPR55) and transient receptor potential vanilloid 1 (TRPV1).
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Wu, Yan-ran, Jia-qin Tang, Wan-nian Zhang, Chun-lin Zhuang, and Ying Shi. "Rational drug design of CB2 receptor ligands: from 2012 to 2021." RSC Advances 12, no. 54 (2022): 35242–59. http://dx.doi.org/10.1039/d2ra05661e.
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Ye, Lingyan, Zheng Cao, Weiwei Wang, and Naiming Zhou. "New Insights in Cannabinoid Receptor Structure and Signaling." Current Molecular Pharmacology 12, no. 3 (July 29, 2019): 239–48. http://dx.doi.org/10.2174/1874467212666190215112036.
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Background: Cannabinoid has long been used for medicinal purposes. Cannabinoid signaling has been considered the therapeutic target for treating pain, addiction, obesity, inflammation, and other diseases. Recent studies have suggested that in addition to CB1 and CB2, there are non-CB1 and non-CB2 cannabinoid-related orphan GPCRs including GPR18, GPR55, and GPR119. In addition, CB1 and CB2 display allosteric binding and biased signaling, revealing correlations between biased signaling and functional outcomes. Interestingly, new investigations have indicated that CB1 is functionally present within the mitochondria of striated and heart muscles directly regulating intramitochondrial signaling and respiration. Conclusion: In this review, we summarize the recent progress in cannabinoid-related orphan GPCRs, CB1/CB2 structure, Gi/Gs coupling, allosteric ligands and biased signaling, and mitochondria-localized CB1, and discuss the future promise of this research.
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Howlett, Allyn C., Barbara Berglund, and Lawrence S. Melvin. "Cannabinoid Receptor Agonists and Antagonists." Current Pharmaceutical Design 1, no. 3 (October 1995): 343–54. http://dx.doi.org/10.2174/1381612801666220918164118.
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Research on the cannabinoid natural products and synthetic drugs has been bolstered recently by major breakthroughs in the understanding of the biochemical pathways and the production of significant new tools in the form of novel chemical structures. Cannabinoid receptors are now defined pharmacologically, anatomically, and at the molecular level as belonging to the seven transmembrane spanning G protein coupled receptor superfarnily. Currently recognized receptor subtypes include the CB1 and CBJ(a) splice variants, found predominantly in the brain, and the CB2 subtype, identified in cells of immunologic origin. Three structurally different classes of cannabinoid receptor agonists have been characterized and serve as pharmacological tools most frequently used to explore drug-receptor interactions both in vitro and in vivo9. -THC and HU-210 characterize the classical ABC-tricyclic cannabinoid structures. CP-55,940 is a prototype of the nonclassical AC-bicyclic synthetic cannabinoids, and CP-55,244 is an ACD-bicyclic structure that defines a novel receptor binding region. WIN-55212-2 is a prototype agonist in the aminoalkylindole series of cannabimimetic structures. Arachidonylethanolamide (anandamide) is an eicosanoid natural product that acts as a cannabinoid agonist. With the advent of a high potency, CB1 receptor-selective antagonist, SR141716A, it is possible that novel cannabinoid receptor subtypes will be able to be distinguished pharmacologically.
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Ellert-Miklaszewska, Aleksandra, Iwona Anna Ciechomska, and Bozena Kaminska. "Synthetic Cannabinoids Induce Autophagy and Mitochondrial Apoptotic Pathways in Human Glioblastoma Cells Independently of Deficiency in TP53 or PTEN Tumor Suppressors." Cancers 13, no. 3 (January 22, 2021): 419. http://dx.doi.org/10.3390/cancers13030419.
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Glioblastomas (GBMs) are aggressive brain tumors with frequent genetic alterations in TP53 and PTEN tumor suppressor genes rendering resistance to standard chemotherapeutics. Cannabinoid type 1 and 2 (CB1/CB2) receptor expression in GBMs and antitumor activity of cannabinoids in glioma cells and animal models, raised promises for a targeted treatment of these tumors. The susceptibility of human glioma cells to CB2-agonists and their mechanism of action are not fully elucidated. We determined CB1 and CB2 expression in 14 low-grade and 21 high-grade tumor biopsies, GBM-derived primary cultures and established cell lines. The non-selective CB receptor agonist WIN55,212-2 (but not its inactive enantiomer) or the CB2-selective agonist JWH133 induced apoptosis in patient-derived glioma cultures and five established glioma cell lines despite p53 and/or PTEN deficiency. Growth inhibitory efficacy of cannabinoids correlated with CB1/CB2 expression (EC50 WIN55,212-2: 7.36–15.70 µM, JWH133: 12.15–143.20 µM). Treatment with WIN55,212-2 or JWH133 led to activation of the apoptotic mitochondrial pathway and DNA fragmentation. Synthetic cannabinoid action was associated with the induction of autophagy and knockdown of autophagy genes augmented cannabinoid-induced apoptotic cell death. The high susceptibility of human glioblastoma cells to synthetic cannabinoids, despite genetic defects contributing to apoptosis resistance, makes cannabinoids promising anti-glioma therapeutics.
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Potenzieri, Carl, Thaddeus S. Brink, Cholawat Pacharinsak, and Donald A. Simone. "Cannabinoid Modulation of Cutaneous Aδ Nociceptors During Inflammation." Journal of Neurophysiology 100, no. 5 (November 2008): 2794–806. http://dx.doi.org/10.1152/jn.90809.2008.
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Previous studies have demonstrated that locally administered cannabinoids attenuate allodynia and hyperalgesia through activation of peripheral cannabinoid receptors (CB1 and CB2). However, it is currently unknown if cannabinoids alter the response properties of nociceptors. In the present study, correlative behavioral and in vivo electrophysiological studies were conducted to determine if peripheral administration of the cannabinoid receptor agonists arachidonyl-2′-chloroethylamide (ACEA) or (R)-(+)-methanandamide (methAEA) could attenuate mechanical allodynia and hyperalgesia, and decrease mechanically evoked responses of Aδ nociceptors. Twenty-four hours after intraplantar injection of complete Freund's adjuvant (CFA), rats exhibited allodynia (decrease in paw withdrawal threshold) and hyperalgesia (increase in paw withdrawal frequency), which were attenuated by both ACEA and methAEA. The antinociceptive effects of these cannabinoids were blocked by co-administration with the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) but not with the CB2 receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-y l](4-methoxyphenyl)methanone (AM630). ACEA and methAEA did not produce antinociception under control, non-inflamed conditions 24 h after intraplantar injection of saline. In parallel studies, recordings were made from cutaneous Aδ nociceptors from inflamed or control, non-inflamed skin. Both ACEA and methAEA decreased responses evoked by mechanical stimulation of Aδ nociceptors from inflamed skin but not from non-inflamed skin, and this decrease was blocked by administration of the CB1 receptor antagonist AM251. These results suggest that attenuation of mechanically evoked responses of Aδ nociceptors contributes to the behavioral antinociception produced by activation of peripheral CB1 receptors during inflammation.
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Rohbeck, Elisabeth, Juergen Eckel, and Tania Romacho. "Cannabinoid Receptors in Metabolic Regulation and Diabetes." Physiology 36, no. 2 (March 1, 2021): 102–13. http://dx.doi.org/10.1152/physiol.00029.2020.
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There is an urgent need for developing effective drugs to combat the obesity and Type 2 diabetes mellitus epidemics. The endocannabinoid system plays a major role in energy homeostasis. It comprises the cannabinoid receptors 1 and 2 (CB1 and CB2), endogenous ligands called endocannabinoids and their metabolizing enzymes. Because the CB1 receptor is overactivated in metabolic alterations, pharmacological blockade of the CB1 receptor arose as a promising candidate to treat obesity. However, because of the wide distribution of CB1 receptors in the central nervous system, their negative central effects halted further therapeutic use. Although the CB2 receptor is mostly peripherally expressed, its role in metabolic homeostasis remains unclear. This review discusses the potential of CB1 and CB2 receptors at the peripheral level to be therapeutic targets in metabolic diseases. We focus on the impact of pharmacological intervention and/or silencing on peripheral cannabinoid receptors in organs/tissues relevant for energy homeostasis. Moreover, we provide a perspective on novel therapeutic strategies modulating these receptors. Targeting CB1 with peripherally restricted antagonists, neutral antagonists, inverse agonists, or monoclonal antibodies could represent successful strategies. CB2 agonism has shown promising results at preclinical level. Beyond classic antagonism and agonism targeting orthosteric sites, the recently described crystal structures of CB1 and CB2 open new possibilities for therapeutic interventions with negative and positive allosteric modulators. The challenge of simultaneously targeting CB1 and CB2 might be possible by developing dual-steric ligands. The future will tell whether these promising strategies result in a renaissance of the cannabinoid receptors as therapeutic targets in metabolic diseases.
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Asproni, Battistina, Gabriele Murineddu, Paola Corona, and Gérard A. Pinna. "Tricyclic Pyrazole-Based Compounds as Useful Scaffolds for Cannabinoid CB1/CB2 Receptor Interaction." Molecules 26, no. 8 (April 7, 2021): 2126. http://dx.doi.org/10.3390/molecules26082126.
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Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include analgesic activity, bodyweight reduction, the antiemetic effect, the reduction of intraocular pressure and many others, which appear correlated to the affinity of cannabinoids towards CB1 and/or CB2 receptors. Within the search aiming to identify novel chemical scaffolds for cannabinoid receptor interaction, the CB1 antagonist/inverse agonist pyrazole-based derivative rimonabant has been modified, giving rise to several tricyclic pyrazole-based compounds, most of which endowed of high affinity and selectivity for CB1 or CB2 receptors. The aim of this review is to present the synthesis and summarize the SAR study of such tricyclic pyrazole-based compounds, evidencing, for some derivatives, their potential in the treatment of neuropathic pain, obesity or in the management of glaucoma.
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Zhang, Xuefeng, Jian Feng Wang, Yehoshua Maor, George Kunos, and Jerome E. Groopman. "Endogenous Cannabinoid-Like Arachidonoyl Serine Induces Angiogenesis through Novel Pathways." Blood 106, no. 11 (November 16, 2005): 3690. http://dx.doi.org/10.1182/blood.v106.11.3690.3690.
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Abstract Cannabinoid effects on the central nervous system have been well-described and include altered cognition, memory, motor function, and concentration. Studies have also shown that marijuana and its primary active constituent, THC (Tetrahydrocannabinol), can be salubrious in treating diverse medical conditions such as chemotherapy-induced nausea, HIV cachexia, glaucoma, and chronic pain. Recently, cannabinoids have been shown in animal models to inhibit the growth and metastasis of certain tumors through their effects on angiogenesis. There are also animal data showing that cannabinoids can alter circulatory responses by their effects on vascular tissues. However, the mechanisms involved in this modulation of angiogenesis and vascular function are not well elucidated. Δ9-THC binds with similar affinity to both CB1 and CB2, two well characterized G-protein-coupled receptors for cannabinoids. Both CB1 and CB2 are expressed to varying degrees by endothelium based on the origin of the tissue. Considerable evidence, including data from CB1/CB2 knockout mice, suggests that there is an additional endothelial cannabinoid receptor besides CB1 and CB2. This receptor has not yet been identified. We found that Δ9-THC inhibited in vitro angiogenesis in a dose dependent manner in the Matrigel assay. Δ9-THC reduced the expression of VEGFR-3 as well as the secretion of its cognate ligand VEGF-C. Blocking of the CB1 and CB2 receptors with their respective antagonists AM251 and AM630, individually or in combination, only partially reversed the THC-mediated inhibition of angiogenesis. However, pretreatment with N-Arachidonoyl Serine (ARA-S) or O-1918 [(−)-4-(3-3, 4-trans-p-menthadien-(1, 8)-yl)-orcinol], antagonists of the putative third endothelial cannabinoid receptor, significantly protected the endothelium from the inhibitory effects of Δ9-THC. In parallel, we found that abn-cbd [(−)-4-(3-3, 4-trans-p-menthadien-[1, 8]-yl)-olivetol], a selective agonist of this putative endothelial cannabinoid receptor, also inhibited in vitro angiogenesis. Pretreatment with ARA-S or O-1918 blocked the abn-cbd-mediated inhibition of angiogenesis, whereas pretreatment with AM251 or AM630 did not show significant protective effects following abn-cbd exposure. To clarify the mechanisms involved in this process, we studied the signaling pathways of cell growth and survival in endothelium following these treatments. We observed that both the ARA-S and O-1918 treatments activated ERK1/2 MAP kinase and Akt. Moreover, endothelial cells pretreated with ARA-S or O-1918 followed by THC treatment sustained significantly higher levels of ERK1/2 MAP kinase and Akt phosphorylation as compared to the THC-stimulated cells pretreated with vehicle control, the CB1 antagonist AM251, or the CB2 antagonist AM630. In addition, significantly more VEGF-C was detected in the culture supernatants of cells pretreated with the antagonists ARA-S and O-1918. ARA-S showed stronger effects than O-1918 in these studies. These results indicate that cannabinoids may regulate angiogenesis through novel pathways that are not mediated by the CB1 and CB2 receptors. Further understanding of such pathways may allow for therapeutic intervention with cannabinoids in disease states associated with neo-angiogenesis, like hematologic malignancies and solid tumors.
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Sapundzhi, Fatima, Tatyana Dzimbova, Nevena Pencheva, and Peter Milanov. "Computer modeling of Cannabinoid receptor type 1." ITM Web of Conferences 16 (2018): 02008. http://dx.doi.org/10.1051/itmconf/20181602008.
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Cannabinoid receptors are important class of receptors as they are involved in various physiological processes such as appetite, pain-sensation, mood, and memory. It is important to design receptor-selective ligands in order to treat a particular disorder. The aim of the present study is to model the structure of cannabinoid receptor CB1 and to perform docking between obtained models and known ligands. Two models of CBR1 were prepared with two different methods (Modeller of Chimera and MOE). They were used for docking with GOLD 5.2. It was established a high correlation between inhibitory constant Ki of CB1 cannabinoid ligands and the ChemScore scoring function of GOLD, which concerns both models. This suggests that the models of the CB1 receptors obtained could be used for docking studies and in further investigation and design of new potential, selective and active cannabinoids with the desired effects.
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Maslov, L. N., and R. S. Karpov. "Prospects for the Use of Cannabinoid Receptor Ligands for the Treatment of Metabolic Syndrome and Atherosclerosis: Analysis of Experimental and Clinical Data." Annals of the Russian academy of medical sciences 72, no. 1 (February 1, 2017): 59–65. http://dx.doi.org/10.15690/vramn779.
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An antagonist of central cannabinoid CB1 receptors rimonabant causes weight loss in patients with obesity and metabolic syndrome, improves blood lipid parameters, increases the adiponectin level, decreases the rate of glucose and glycosylated hemoglobin in patients with diabetes mellitustype-2. However, rimonabant adverse effects include depression, anxiety, nausea, and dizziness which are apparently due to the blockade of central CB1 receptors. In mice with a high-calorie diet, we defined that the blockade of peripheral CB1 receptors prevents obesity, steatosis of the liver, improves lipid and carbohydrate metabolism. Experimental studies suggest that peripheral CB2 receptor agonists have antiatherogenic effect. To validate the expediency of clinical research of CB2 receptor agonists in patients with atherosclerosis the comparative analysis of antiatherogenic properties of cannabinoids should be performed. In addition, experiments are needed on the combination use of cannabinoids with well-known antiatherogenic agents, such as statins.
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Tang, Xinru, Zheng Liu, Xiaoqing Li, Jing Wang, and Liliang Li. "Cannabinoid Receptors in Myocardial Injury: A Brother Born to Rival." International Journal of Molecular Sciences 22, no. 13 (June 26, 2021): 6886. http://dx.doi.org/10.3390/ijms22136886.
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Cannabinoid receptors typically include type 1 (CB1) and type 2 (CB2), and they have attracted extensive attention in the central nervous system (CNS) and immune system. Due to more in-depth studies in recent years, it has been found that the typical CB1 and CB2 receptors confer functional importance far beyond the CNS and immune system. In particular, many works have reported the critical involvement of the CB1 and CB2 receptors in myocardial injuries. Both pharmacological and genetic approaches have been used for studying CB1 and CB2 functions in these studies, revealing that the brother receptors have many basic differences and sometimes antagonistic functions in a variety of myocardial injuries, despite some sequence or location identity they share. Herein, we introduce the general differences of CB1 and CB2 cannabinoid receptors, and summarize the functional rivalries between the two brother receptors in the setting of myocardial injuries. We point out the importance of individual receptor-based modulation, instead of dual receptor modulators, when treating myocardial injuries.
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Ji, Xiaoyu, Yang Zeng, and Jie Wu. "The CB2 Receptor as a Novel Therapeutic Target for Epilepsy Treatment." International Journal of Molecular Sciences 22, no. 16 (August 20, 2021): 8961. http://dx.doi.org/10.3390/ijms22168961.
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Epilepsy is characterized by repeated spontaneous bursts of neuronal hyperactivity and high synchronization in the central nervous system. It seriously affects the quality of life of epileptic patients, and nearly 30% of individuals are refractory to treatment of antiseizure drugs. Therefore, there is an urgent need to develop new drugs to manage and control refractory epilepsy. Cannabinoid ligands, including selective cannabinoid receptor subtype (CB1 or CB2 receptor) ligands and non-selective cannabinoid (synthetic and endogenous) ligands, may serve as novel candidates for this need. Cannabinoid appears to regulate seizure activity in the brain through the activation of CB1 and CB2 cannabinoid receptors (CB1R and CB2R). An abundant series of cannabinoid analogues have been tested in various animal models, including the rat pilocarpine model of acquired epilepsy, a pentylenetetrazol model of myoclonic seizures in mice, and a penicillin-induced model of epileptiform activity in the rats. The accumulating lines of evidence show that cannabinoid ligands exhibit significant benefits to control seizure activity in different epileptic models. In this review, we summarize the relationship between brain CB2 receptors and seizures and emphasize the potential mechanisms of their therapeutic effects involving the influences of neurons, astrocytes, and microglia cells. The unique features of CB2Rs, such as lower expression levels under physiological conditions and high inducibility under epileptic conditions, make it an important target for future research on drug-resistant epilepsy.
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Sachdev, Shivani, Rochelle Boyd, Natasha L. Grimsey, Marina Santiago, and Mark Connor. "Brodifacoum does not modulate human cannabinoid receptor-mediated hyperpolarization of AtT20 cells or inhibition of adenylyl cyclase in HEK 293 cells." PeerJ 7 (September 25, 2019): e7733. http://dx.doi.org/10.7717/peerj.7733.
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BackgroundSynthetic cannabinoids are a commonly used class of recreational drugs that can have significant adverse effects. There have been sporadic reports of co-consumption of illicit drugs with rodenticides such as warfarin and brodifacoum (BFC) over the past 20 years but recently, hundreds of people have been reported to have been poisoned with a mixture of synthetic cannabinoids and BFC. We have sought to establish whether BFC directly affects cannabinoid receptors, or their activation by the synthetic cannabinoid CP55940 or the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC).MethodsThe effects of BFC on the hyperpolarization of wild type AtT20 cells, or AtT20 cells stably expressing human CB1- or CB2- receptors, were studied using a fluorescent assay of membrane potential. The effect of BFC on CB1- and CB2-mediated inhibition of forskolin-stimulated adenylyl cyclase (AC) activation was measured using a BRET assay of cAMP levels in HEK 293 cells stably expressing human CB1or CB2.ResultsBFC did not activate CB1or CB2receptors, or affect the hyperpolarization of wild type AtT20 cells produced by somatostatin. BFC (1 µM) did not affect the hyperpolarization of AtT20-CB1or AtT20-CB2cells produced by CP55940 or Δ9-THC. BFC (1 µM) did not affect the inhibition of forskolin-stimulated AC activity by CP55940 in HEK 293 cells expressing CB1or CB2. BFC (1 µM) also failed to affect the desensitization of CB1and CB2signaling produced by prolonged (30 min) application of CP55940 or Δ9-THC to AtT20 cells.DiscussionBFC is not a cannabinoid receptor agonist, and appeared not to affect cannabinoid receptor activation. Our data suggests there is no pharmacodynamic rationale for mixing BFC with synthetic cannabinoids; however, it does not speak to whether BFC may affect synthetic cannabinoid metabolism or biodistribution. The reasons underlying the mixing of BFC with synthetic cannabinoids are unknown, and it remains to be established whether the “contamination” was deliberate or accidental. However, the consequences for people who ingested the mixture were often serious, and sometimes fatal, but this seems unlikely to be due to BFC action at cannabinoid receptors.
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Sun, Y., S. P. H. Alexander, D. A. Kendall, and A. J. Bennett. "Cannabinoids and PPARα signalling." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1095–97. http://dx.doi.org/10.1042/bst0341095.
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Cannabinoids have been shown to possess anti-inflammatory and neuroprotective properties, which were proposed to occur mainly via activation of the G-protein-coupled receptor CB1 (cannabinoid receptor 1). Recently, certain cannabinoids have been reported to be ligands for members of the nuclear receptor transcription factor superfamily known as PPARs (peroxisome-proliferator-activated receptors). This review summarizes the evidence for cannabinoid activation of PPARs and identifies a new intracellular target for cannabinoids as therapeutic agents for neuroprotective treatment.
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Silva, Guillermo B., Douglas K. Atchison, Luis I. Juncos, and Néstor H. García. "Anandamide inhibits transport-related oxygen consumption in the loop of Henle by activating CB1 receptors." American Journal of Physiology-Renal Physiology 304, no. 4 (February 15, 2013): F376—F381. http://dx.doi.org/10.1152/ajprenal.00239.2012.
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The energy required for active Na chloride reabsorption in the thick ascending limb (TAL) depends on oxygen consumption and oxidative phosphorylation (OXP). In other cells, Na transport is inhibited by the endogenous cannabinoid anandamide through the activation of the cannabinoid receptors (CB) type 1 and 2. However, it is unclear whether anandamide alters TAL transport and the mechanisms that could be involved. We hypothesized that anandamide inhibits TAL transport via activation of CB1 receptors and NO. For this, we measured oxygen consumption (QO2) in TAL suspensions to monitor the anandamide effects on transport and OXP. Anandamide reduced QO2 in a concentration-dependent manner. During Na-K-2Cl cotransport and Na/H exchange inhibition, anandamide did not inhibit TAL QO2. To test the role of the cannabinoid receptors, we used specific agonists and antagonists of CB1 and CB2 receptors. The CB1-selective agonist WIN55212–2 reduced QO2 in a concentration-dependent manner. Also, the CB1 receptor antagonist rimonabant blocked the effect of anandamide on QO2. In contrast, the CB2-selective agonist JHW-133 had no effect on QO2, while the CB2 receptor antagonist AM-630 failed to block the anandamide effects on QO2. To confirm these results, we measured CB1 and CB2 receptor expression and only CB1 expression was detected. Because CB1 receptors are strong nitric oxide synthase (NOS) stimulators and NO inhibits transport in TALs, we evaluated the role of NO. Anandamide stimulated NO production and the NOS inhibitor NG-nitro-l-arginine methyl ester blocked the anandamide effects on QO2. We conclude that anandamide inhibits TAL Na transport-related QO2 via activation of CB1 receptor and NOS.
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Haddad, Mansour. "The Impact of CB1 Receptor on Nuclear Receptors in Skeletal Muscle Cells." Pathophysiology 28, no. 4 (October 5, 2021): 457–70. http://dx.doi.org/10.3390/pathophysiology28040029.
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Cannabinoids are abundant signaling compounds; their influence predominantly arises via engagement with the principal two G-protein-coupled cannabinoid receptors, CB1 and CB2. One suggested theory is that cannabinoids regulate a variety of physiological processes within the cells of skeletal muscle. Earlier publications have indicated that expression of CB1 receptor mRNA and protein has been recognized within myotubes and tissues of skeletal muscle from both murines and humans, thus representing a potentially significant pathway which plays a role in the control of skeletal muscular activities. The part played by CB1 receptor activation or inhibition with respect to these functions and relevant to targets in the periphery, especially skeletal muscle, is not fully delineated. Thus, the aim of the current research was to explore the influence of CB1 receptor stimulation and inhibition on downstream signaling of the nuclear receptor, NR4A, which regulates the immediate impacts of arachidonyl-2′-chloroethylamide (ACEA) and/or rimonabant in the cells of skeletal muscle. Murine L6 skeletal muscle cells were used in order to clarify additional possible molecular signaling pathways which contribute to alterations in the CB1 receptor. Skeletal muscle cells have often been used; it is well-documented that they express cannabinoid receptors. Quantitative real-time probe-based polymerase chain reaction (qRT-PCR) assays are deployed in order to assess the gene expression characteristics of CB1 receptor signaling. In the current work, it is demonstrated that skeletal muscle cells exhibit functional expression of CB1 receptors. This can be deduced from the qRT-PCR assays; triggering CB1 receptors amplifies both NR4A1 and NR4A3 mRNA gene expression. The impact of ACEA is inhibited by the selective CB1 receptor antagonist, rimonabant. The present research demonstrated that 10 nM of ACEA notably amplified mRNA gene expression of NR4A1 and NR4A3; this effect was suppressed by the addition of 100 nM rimonabant. Furthermore, the CB1 receptor antagonist led to the downregulation of mRNA gene expression of NR4A1, NR4A2 and NR4A3. In conclusion, in skeletal muscle, CB1 receptors were recognized to be important moderators of NR4A1 and NR4A3 mRNA gene expression; these actions may have possible clinical benefits. Thus, in skeletal muscle cells, a possible physiological expression of CB1 receptors was identified. It is as yet unknown whether these CB1 receptors contribute to pathways underlying skeletal muscle biological function and disease processes. Further research is required to fully delineate their role(s).
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Xu, Kangtai, Yifei Wu, Zhuangzhuang Tian, Yuanfan Xu, Chaoran Wu, and Zilong Wang. "Microglial Cannabinoid CB2 Receptors in Pain Modulation." International Journal of Molecular Sciences 24, no. 3 (January 25, 2023): 2348. http://dx.doi.org/10.3390/ijms24032348.
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Pain, especially chronic pain, can strongly affect patients’ quality of life. Cannabinoids ponhave been reported to produce potent analgesic effects in different preclinical pain models, where they primarily function as agonists of Gi/o protein-coupled cannabinoid CB1 and CB2 receptors. The CB1 receptors are abundantly expressed in both the peripheral and central nervous systems. The central activation of CB1 receptors is strongly associated with psychotropic adverse effects, thus largely limiting its therapeutic potential. However, the CB2 receptors are promising targets for pain treatment without psychotropic adverse effects, as they are primarily expressed in immune cells. Additionally, as the resident immune cells in the central nervous system, microglia are increasingly recognized as critical players in chronic pain. Accumulating evidence has demonstrated that the expression of CB2 receptors is significantly increased in activated microglia in the spinal cord, which exerts protective consequences within the surrounding neural circuitry by regulating the activity and function of microglia. In this review, we focused on recent advances in understanding the role of microglial CB2 receptors in spinal nociceptive circuitry, highlighting the mechanism of CB2 receptors in modulating microglia function and its implications for CB2 receptor- selective agonist-mediated analgesia.
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Hossain, Mohammad Zakir, Hiroshi Ando, Shumpei Unno, and Junichi Kitagawa. "Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain." International Journal of Molecular Sciences 21, no. 4 (February 20, 2020): 1423. http://dx.doi.org/10.3390/ijms21041423.
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Neuropathic pain conditions including neuropathic orofacial pain (NOP) are difficult to treat. Contemporary therapeutic agents for neuropathic pain are often ineffective in relieving pain and are associated with various adverse effects. Finding new options for treating neuropathic pain is a major priority in pain-related research. Cannabinoid-based therapeutic strategies have emerged as promising new options. Cannabinoids mainly act on cannabinoid 1 (CB1) and 2 (CB2) receptors, and the former is widely distributed in the brain. The therapeutic significance of cannabinoids is masked by their adverse effects including sedation, motor impairment, addiction and cognitive impairment, which are thought to be mediated by CB1 receptors in the brain. Alternative approaches have been developed to overcome this problem by selectively targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoids that may be locally synthesized on demand at sites where their actions are pertinent. Many preclinical studies have reported that these strategies are effective for treating neuropathic pain and produce no or minimal side effects. Recently, we observed that inhibition of degradation of a major endocannabinoid, 2-arachydonoylglycerol, can attenuate NOP following trigeminal nerve injury in mice. This review will discuss the above-mentioned alternative approaches that show potential for treating neuropathic pain including NOP.
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Twitchell, W., S. Brown, and K. Mackie. "Cannabinoids Inhibit N- and P/Q-Type Calcium Channels in Cultured Rat Hippocampal Neurons." Journal of Neurophysiology 78, no. 1 (July 1, 1997): 43–50. http://dx.doi.org/10.1152/jn.1997.78.1.43.
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Twitchell, W., S. Brown, and K. Mackie. Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J. Neurophysiol. 78: 43–50, 1997. Cannabinoids and their analogues have been found to inhibit N- and P/Q-type Ca2+ currents in cell lines and sympathetic neurons transfected with cannabinoid CB1 receptor. However, the effects of cannabinoids on Ca2+ currents in the CNS are largely unexplored. In this study we investigated whether these compounds inhibit Ca2+ channels in cultured rat hippocampal neurons. With the use of antibodies directed against the amino-terminus of the CB1 receptor, we found that in 5-day cultures pyramidally shaped neurons expressed somatic CB1 receptors, whereas in 4-wk cultures the receptor was predomintely located on neurites. In early cultures, the cannabimimetic WIN 55,212-2 reversibly inhibited whole cell Ba2+ current in a concentration-dependent ( K 1/2 = 21 nM) and pertussis-toxin-sensitive fashion. Inhibition was reduced by the CB1 antagonist SR141716. The current was unaffected by the nonpsychoactive enantiomer WIN 55,212-3. Maximal inhibition by the nonclassical cannabinoid agonist CP 55,940 and by an endogenous cannabinoid, anandamide, were similar to that seen with maximal concentrations of WIN 55,212-2. The Ba2+ current modulated by cannabinoids was carried by N-type (ω-conotoxin-GVIA-sensitive) and P/Q-type (ω-conotoxin-MVIIC-sensitive) channels. These results demonstrate cannabinoid-receptor-mediated inhibition of distinct Ca2+ channels in central neurons. Because the channels that underlie these currents are chiefly located presynaptically, and are required for evoked neurotransmitter release, our results suggest a major role for cannabinoids (endogenous and exogenous) in the modulation of synaptic transmission at CNS synapses.
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Orazbekov, Yerkebulan, Mohamed A. Ibrahim, Serjan Mombekov, Radhakrishnan Srivedavyasasri, Ubaidilla Datkhayev, Bauyrzhan Makhatov, Narayan D. Chaurasiya, Babu L. Tekwani, and Samir A. Ross. "Isolation and Biological Evaluation of Prenylated Flavonoids from Maclura pomifera." Evidence-Based Complementary and Alternative Medicine 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/1370368.
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Phytochemical analysis of the ethanolic extract of Maclura pomifera fruits yielded four new compounds (I–IV) along with eleven known compounds (V–XV). The crude extract exhibited significant activity towards cannabinoid receptors (CB1: 103.4% displacement; CB2: 68.8% displacement) and possibly allosteric interaction with δ and μ opioid receptors (−49.7 and −53.8% displacement, resp.). Compound I was found to be possibly allosteric for κ and μ opioid receptors (−88.4 and −27.2% displacement, resp.) and showed moderate activity (60.5% displacement) towards CB1 receptor. Compound II exhibited moderate activity towards cannabinoid receptors CB1 and CB2 (47.9 and 42.3% displacement, resp.). The known compounds (V–VIII) exhibited prominent activity towards cannabinoid receptors: pomiferin (V) (IC50 of 2.110 and 1.318 μM for CB1 and CB2, resp.), auriculasin (VI) (IC50 of 8.923 μM for CB1), warangalone (VII) (IC50 of 1.670 and 4.438 μM for CB1 and CB2, resp.), and osajin (VIII) (IC50 of 3.859 and 7.646 μM for CB1 and CB2, resp.). The isolated compounds were also tested for inhibition of human monoamine oxidase-A and monoamine oxidase-B enzymes activities, where all the tested compounds showed fewer inhibitory effects on MAO-A compared to MAO-B activities: auriculasin (VI) (IC50 of 1.91 and 45.98 μM for MAO-B and MAO-A, resp.).
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Kelly, Sara, and Victoria Chapman. "Selective Cannabinoid CB1 Receptor Activation Inhibits Spinal Nociceptive Transmission In Vivo." Journal of Neurophysiology 86, no. 6 (December 1, 2001): 3061–64. http://dx.doi.org/10.1152/jn.2001.86.6.3061.
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Cannabinoid1 (CB1) receptors are located at CNS sites, including the spinal cord, involved in somatosensory processing. Analgesia is one of the tetrad of behaviors associated with cannabinoid agonists. Here, effects of a potent cannabinoid CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA) on evoked responses of dorsal horn neurons in anesthetized rats were investigated. Extracellular recordings of convergent dorsal horn neurons were made in halothane anesthetized Sprague-Dawley rats ( n = 16). Effects of spinal application of ACEA on electrically evoked responses of dorsal horn neurons were studied. Mean maximal effects of 0.5, 5, 50, and 500 ng/50 μl ACEA on the C-fiber-mediated postdischarge response were 79 ± 6, 62 ± 10, and 54 ± 7% ( P < 0.01), 45 ± 6% ( P < 0.01), of control, respectively. ACEA (500 ng/50 μl) also reduced the C-fiber-evoked nonpotentiated responses of neurons (59 ± 9% of control, P < 0.05) and Aδ-fiber-evoked responses of neurons (68 ± 10% of control, P < 0.01). Minor effects of ACEA on Aβ-fiber-evoked responses were observed. Spinal pre-administration of the selective CB1 receptor antagonist SR141716A (0.01 μg/50 μl) significantly reduced effects of ACEA (500 ng/50 μl) on postdischarge responses of dorsal horn neurons. This study demonstrates that spinal CB1 receptors modulate the transmission of C- and Aδ-fiber-evoked responses in anesthetized rats; this may reflect pre- and/or postsynaptic effects of cannabinoids on nociceptive transmission. CB1 receptors inhibit synaptic release of glutamate in rat dorsolateral striatum, a similar mechanism of action may underlie the effects of ACEA on noxious evoked responses of spinal neurons reported here.
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Yang, Yi, Rupali Vyawahare, Melissa Lewis-Bakker, Hance A. Clarke, Albert H. C. Wong, and Lakshmi P. Kotra. "Bioactive Chemical Composition of Cannabis Extracts and Cannabinoid Receptors." Molecules 25, no. 15 (July 30, 2020): 3466. http://dx.doi.org/10.3390/molecules25153466.
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Cannabis is widely used as a therapeutic drug, especially by patients suffering from psychiatric and neurodegenerative diseases. However, the complex interplay between phytocannabinoids and their targets in the human receptome remains largely a mystery, and there have been few investigations into the relationship between the chemical composition of medical cannabis and the corresponding biological activity. In this study, we investigated 59 cannabis samples used by patients for medical reasons. The samples were subjected to extraction (microwave and supercritical carbon dioxide) and chemical analyses, and the resulting extracts were assayed in vitro using the CB1 and CB2 receptors. Using a partial least squares regression analysis, the chemical compositions of the extracts were then correlated to their corresponding cannabinoid receptor activities, thus generating predictive models that describe the receptor potency as a function of major phytocannabinoid content. Using the current dataset, meaningful models for CB1 and CB2 receptor agonism were obtained, and these reveal the insignificant relationships between the major phytocannabinoid content and receptor affinity for CB1 but good correlations between the two at CB2 receptors. These results also explain the anomalies between the receptor activities of pure phytocannabinoids and cannabis extracts. Furthermore, the models for CB1 and CB2 agonism in cannabis extracts predict the cannabinoid receptor activities of individual phytocannabinoids with reasonable accuracy. Here for the first time, we disclose a method to predict the relationship between the chemical composition, including phytocannabinoids, of cannabis extracts and cannabinoid receptor responses.
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Braile, Mariantonia, Simone Marcella, Gianni Marone, Maria Rosaria Galdiero, Gilda Varricchi, and Stefania Loffredo. "The Interplay between the Immune and the Endocannabinoid Systems in Cancer." Cells 10, no. 6 (May 21, 2021): 1282. http://dx.doi.org/10.3390/cells10061282.
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The therapeutic potential of Cannabis sativa has been recognized since ancient times. Phytocannabinoids, endocannabinoids and synthetic cannabinoids activate two major G protein-coupled receptors, subtype 1 and 2 (CB1 and CB2). Cannabinoids (CBs) modulate several aspects of cancer cells, such as apoptosis, autophagy, proliferation, migration, epithelial-to-mesenchymal transition and stemness. Moreover, agonists of CB1 and CB2 receptors inhibit angiogenesis and lymphangiogenesis in vitro and in vivo. Low-grade inflammation is a hallmark of cancer in the tumor microenvironment (TME), which contains a plethora of innate and adaptive immune cells. These cells play a central role in tumor initiation and growth and the formation of metastasis. CB2 and, to a lesser extent, CB1 receptors are expressed on a variety of immune cells present in TME (e.g., T cells, macrophages, mast cells, neutrophils, NK cells, dendritic cells, monocytes, eosinophils). The activation of CB receptors modulates a variety of biological effects on cells of the adaptive and innate immune system. The expression of CB2 and CB1 on different subsets of immune cells in TME and hence in tumor development is incompletely characterized. The recent characterization of the human cannabinoid receptor CB2-Gi signaling complex will likely aid to design potent and specific CB2/CB1 ligands with therapeutic potential in cancer.
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Pagano Zottola, Antonio C., Ilenia Severi, Astrid Cannich, Philippe Ciofi, Daniela Cota, Giovanni Marsicano, Antonio Giordano, and Luigi Bellocchio. "Expression of Functional Cannabinoid Type-1 (CB1) Receptor in Mitochondria of White Adipocytes." Cells 11, no. 16 (August 19, 2022): 2582. http://dx.doi.org/10.3390/cells11162582.
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Via activation of the cannabinoid type-1 (CB1) receptor, endogenous and exogenous cannabinoids modulate important biochemical and cellular processes in adipocytes. Several pieces of evidence suggest that alterations of mitochondrial physiology might be a possible mechanism underlying cannabinoids’ effects on adipocyte biology. Many reports suggest the presence of CB1 receptor mRNA in both white and brown adipose tissue, but the detailed subcellular localization of CB1 protein in adipose cells has so far been scarcely addressed. In this study, we show the presence of the functional CB1 receptor at different subcellular locations of adipocytes from epididymal white adipose tissue (eWAT) depots. We observed that CB1 is located at different subcellular levels, including the plasma membrane and in close association with mitochondria (mtCB1). Functional analysis in tissue homogenates and isolated mitochondria allowed us to reveal that cannabinoids negatively regulate complex-I-dependent oxygen consumption in eWAT. This effect requires mtCB1 activation and consequent regulation of the intramitochondrial cAMP-PKA pathway. Thus, CB1 receptors are functionally present at the mitochondrial level in eWAT adipocytes, adding another possible mechanism for peripheral regulation of energy metabolism.
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Quartilho, Aline, Heriberto P. Mata, Mohab M. Ibrahim, Todd W. Vanderah, Frank Porreca, Alexandros Makriyannis, and T. Philip Malan. "Inhibition of Inflammatory Hyperalgesia by Activation of Peripheral CB2Cannabinoid Receptors." Anesthesiology 99, no. 4 (October 1, 2003): 955–60. http://dx.doi.org/10.1097/00000542-200310000-00031.
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Background Cannabinoid receptor agonists inhibit inflammatory hyperalgesia in animal models. Nonselective cannabinoid receptor agonists also produce central nervous system (CNS) side effects. Agonists selective for CB2 cannabinoid receptors, which are not found in the CNS, do not produce the CNS effects typical of nonselective cannabinoid receptor agonists but do inhibit acute nociception. The authors used the CB2 receptor-selective agonist AM1241 to test the hypothesis that selective activation of peripheral CB2 receptors inhibits inflammatory hyperalgesia. Methods Rats were injected in the hind paw with carrageenan or capsaicin. Paw withdrawal latencies were measured using a focused thermal stimulus. The effects of peripheral CB2 receptor activation were determined by using local injection of AM1241. CB2 receptor mediation of the actions of AM1241 was shown by using the CB2 receptor-selective antagonist AM630 and the CB1 receptor-selective antagonist AM251. Results AM1241 fully reversed carrageenan-induced inflammatory thermal hyperalgesia when injected into the inflamed paw. In contrast, AM1241 injected into the contralateral paw had no effect, showing that its effects were local. AM1241 also reversed the local edema produced by hind paw carrageenan injection. The effects of AM1241 were reversed by the CB2 receptor-selective antagonist AM630, but not by the CB1 receptor-selective antagonist AM251. AM1241 also inhibited flinching and thermal hyperalgesia produced by hind paw capsaicin injection. Conclusions Local, peripheral CB2 receptor activation inhibits inflammation and inflammatory hyperalgesia. These results suggest that peripheral CB2 receptors may be an appropriate target for eliciting relief of inflammatory pain without the CNS effects of nonselective cannabinoid receptor agonists.
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Huffman, J. W. "Cannabimimetic lndoles, Pyrroles and lndenes." Current Medicinal Chemistry 6, no. 8 (August 1999): 705–20. http://dx.doi.org/10.2174/0929867306666220401125055.
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In the course of efforts to develop new nonsteroidal antiinflammatory agents, it was discovered that 1-aminoalkyl-3-aroylindoles have affinity for the cannabinoid brain (CB1 ) receptor. This led to the synthesis of well over 100 cannabimimetic aminoalkylindoles by the group at Sterling Winthrop, and to the development of structure-activity relationships (SAR) for these compounds. These SAR require a heterocyclic aminoethyl group attached to the indole nitrogen, and a 1-naphthoyl group at C-3 for significant receptor affinity. Other workers subsequently demonstrated that an aminoalkyl group was not necessary for cannabinoid activity, but that an N-alkyl group of four to six carbons was sufficient. This led to the discovery that 1-propyl-3-(1-naphthoyl)indole is a selective ligand for the peripheral cannabinoid (CB2) receptor, and to the development of a series of cannabimimetic pyrroles. Comprehensive SAR for this group of cannabinoids have been developed. Two groups have described cannabimimetic indenes, which have been employed as rigid models for the receptor interactions of cannabimimetic indoles with the CB1 receptor. There is some evidence that the indoles interact at a somewhat different site on the receptor than traditional cannabinoids.
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Di MARZO, Vincenzo, Dominique MELCK, Pierangelo ORLANDO, Tiziana BISOGNO, Orna ZAGOORY, Maurizio BIFULCO, Zvi VOGEL, and Luciano de PETROCELLIS. "Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells." Biochemical Journal 358, no. 1 (August 8, 2001): 249–55. http://dx.doi.org/10.1042/bj3580249.
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Palmitoylethanolamide (PEA) has been shown to act in synergy with anandamide (arachidonoylethanolamide; AEA), an endogenous agonist of cannabinoid receptor type 1 (CB1). This synergistic effect was reduced by the CB2 cannabinoid receptor antagonist SR144528, although PEA does not activate either CB1 or CB2 receptors. Here we show that PEA potently enhances the anti-proliferative effects of AEA on human breast cancer cells (HBCCs), in part by inhibiting the expression of fatty acid amide hydrolase (FAAH), the major enzyme catalysing AEA degradation. PEA (1–10μM) enhanced in a dose-related manner the inhibitory effect of AEA on both basal and nerve growth factor (NGF)-induced HBCC proliferation, without inducing any cytostatic effect by itself. PEA (5μM) decreased the IC50 values for AEA inhibitory effects by 3–6-fold. This effect was not blocked by the CB2 receptor antagonist SR144528, and was not mimicked by a selective agonist of CB2 receptors. PEA enhanced AEA-evoked inhibition of the expression of NGF Trk receptors, which underlies the anti-proliferative effect of the endocannabinoid on NGF-stimulated MCF-7 cells. The effect of PEA was due in part to inhibition of AEA degradation, since treatment of MCF-7 cells with 5μM PEA caused a ∼ 30–40% down-regulation of FAAH expression and activity. However, PEA also enhanced the cytostatic effect of the cannabinoid receptor agonist HU-210, although less potently than with AEA. PEA did not modify the affinity of ligands for CB1 or CB2 receptors, and neither did it alter the CB1/CB2-mediated inhibitory effect of AEA on adenylate cyclase type V, nor the expression of CB1 and CB2 receptors in MCF-7 cells. We suggest that long-term PEA treatment of cells may positively affect the pharmacological activity of AEA, in part by inhibiting FAAH expression.
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YAZULLA, STEPHEN, KEITH M. STUDHOLME, HELEN H. McINTOSH, and SHIH-FANG FAN. "Cannabinoid receptors on goldfish retinal bipolar cells: Electron-microscope immunocytochemistry and whole-cell recordings." Visual Neuroscience 17, no. 3 (May 2000): 391–401. http://dx.doi.org/10.1017/s0952523800173079.
Full textAbstract:
Cannabinoid CB1 receptors are distributed throughout the CNS and interact with GABA, glutamate, and dopamine systems. Cannabinoids have effects on the visual system, some of which may have a retinal component, particularly the enhancement of photosensitivity. We used immunocytochemistry and whole-cell recording to study cannabinoids in the goldfish retina. Immunoblots of an antiserum against amino acids (1-14) of the rat CB1 receptor produced a single band in goldfish retina at about 70 kDa. Light microscope immunocytochemistry of CB1 receptor immunoreactivity (CB1R-IR) revealed intense staining of Müller cells and weaker staining of ON bipolar cells (verified with double labeling with PKC-IR) and the outer and inner plexiform layers. Ultrastructural analysis revealed that CB1R-IR was localized intracellularly as well as on the plasma membrane of photoreceptor terminals, bipolar cell terminals and, rarely, amacrine cell boutons. Membrane-associated CB1R-IR was restricted to cone pedicles at sites removed from the synaptic ribbon. Regarding bipolar cells, membrane-associated CB1R-IR was found at 93% of the synaptic terminals in sublamina b (ON-type) and only at 33% of the synaptic terminals in sublamina a (OFF-type). Whole-cell recordings from large ON-type Mb bipolar cells showed that the delayed rectifier (IK(V)) was rapidly and reversibly inhibited by 1 μM of the cannabinoid agonists CP 54490 and (+)-WIN 55212-2, effects blocked completely by the antagonist SR 141716A (1 μM). Inhibition of IK(V) in the Mb bipolar cells by cannabinoids should result in a more tonic ON response to increments of light. As such, cannabinoids may play a role in modulating the temporal aspects of signaling in the retina.
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Benyó, Zoltán, Éva Ruisanchez, Miriam Leszl-Ishiguro, Péter Sándor, and Pál Pacher. "Endocannabinoids in cerebrovascular regulation." American Journal of Physiology-Heart and Circulatory Physiology 310, no. 7 (April 1, 2016): H785—H801. http://dx.doi.org/10.1152/ajpheart.00571.2015.
Full textAbstract:
The cerebral blood flow is tightly regulated by myogenic, endothelial, metabolic, and neural mechanisms under physiological conditions, and a large body of recent evidence indicates that inflammatory pathways have a major influence on the cerebral blood perfusion in certain central nervous system disorders, like hemorrhagic and ischemic stroke, traumatic brain injury, and vascular dementia. All major cell types involved in cerebrovascular control pathways (i.e., smooth muscle, endothelium, neurons, astrocytes, pericytes, microglia, and leukocytes) are capable of synthesizing endocannabinoids and/or express some or several of their target proteins [i.e., the cannabinoid 1 and 2 (CB1 and CB2) receptors and the transient receptor potential vanilloid type 1 ion channel]. Therefore, the endocannabinoid system may importantly modulate the regulation of cerebral circulation under physiological and pathophysiological conditions in a very complex manner. Experimental data accumulated since the late 1990s indicate that the direct effect of cannabinoids on cerebral vessels is vasodilation mediated, at least in part, by CB1 receptors. Cannabinoid-induced cerebrovascular relaxation involves both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium. However, under stress conditions (e.g., in conscious restrained animals or during hypoxia and hypercapnia), cannabinoid receptor activation was shown to induce a reduction of the cerebral blood flow, probably via inhibition of the electrical and/or metabolic activity of neurons. Finally, in certain cerebrovascular pathologies (e.g., subarachnoid hemorrhage, as well as traumatic and ischemic brain injury), activation of CB2 (and probably yet unidentified non-CB1/non-CB2) receptors appear to improve the blood perfusion of the brain via attenuating vascular inflammation.
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Marini, Pietro, Philip Cowie, Ahmet Ayar, Guy S. Bewick, John Barrow, Roger G. Pertwee, Alasdair MacKenzie, and Paolo Tucci. "M3 Receptor Pathway Stimulates Rapid Transcription of the CB1 Receptor Activation through Calcium Signalling and the CNR1 Gene Promoter." International Journal of Molecular Sciences 24, no. 2 (January 9, 2023): 1308. http://dx.doi.org/10.3390/ijms24021308.
Full textAbstract:
In this study, we have investigated a possible mechanism that enables CB1/M3 receptor cross-talk, using SH-SY5Y cells as a model system. Our results show that M3 receptor activation initiates signaling that rapidly upregulates the CNR1 gene, resulting in a greatly potentiated CB1 receptor response to agonists. Calcium homeostasis plays an essential intermediary role in this functional CB1/M3 receptor cross-talk. We show that M3 receptor-triggered calcium release greatly increases CB1 receptor expression via both transcriptional and translational activity, by enhancing CNR1 promoter activity. The co-expression of M3 and CB1 receptors in brain areas such as the nucleus accumbens and amygdala support the hypothesis that the altered synaptic plasticity observed after exposure to cannabinoids involves cross-talk with the M3 receptor subtype. In this context, M3 receptors and their interaction with the cannabinoid system at the transcriptional level represent a potential pharmacogenomic target not only for the develop of new drugs for addressing addiction and tolerance. but also to understand the mechanisms underpinning response stratification to cannabinoids.
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Hughes, Hallmon Victoria, and Victoria Hughes. "Effects of Cannabidiol on Dugesia Dorotocephala Head Regeneration." Athens Journal of Health and Medical Sciences 9, no. 2 (April 28, 2022): 87–94. http://dx.doi.org/10.30958/ajhms.9-2-2.
Full textAbstract:
The endocannabinoid system regulates synaptic transmissions. It is comprised of two G protein-coupled receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), a degradation system and the endocannabinoids, a group of lipidic ligands. The connection between JNK, cannabinoids, and regeneration has led to the hypothesis that cannabinoids impact both regeneration and the levels of the enzymes required for the regenerative process. Thus, by encouraging neoblasts to enter the M phase, cannabinoids would speed up effective regeneration. These regeneration pathways may have implications in cancer research. In addition, CB1 reception suppresses the growth of hepatocellular carcinoma, indicating that the endocannabinoid system may be a possible course of treatment for cancer patients. CB2 receptors in nonimmune cells have revealed the benefits of agonists on osteoporosis and post‐ischemic heart failure. In order to understand the effects of cannabidiol on the regenerative process and neural transmission, we conducted experiments on Dugesia dorotocephala. Dugesia dorotocephala is an ideal candidate for the endocannabinoid model because they are more genetically uniform than most natural populations and their regeneration is specifically tied to cannabinoid receptors. We transversally cut twenty-four Dugesia dorotocephala to analyze differences in head regeneration in solutions with varying amounts of cannabidiol. We found that Dugesia dorotocephala in CBD solutions have a faster rate of head regeneration, yet our results were not statistically significant. The increased rate of head regeneration in Dugesia dorotocephala in CBD solution may be attributed to the stimulation of neoblasts to enter the M-Phase of the cell cycle. Keywords: cannabidiol (CBD), planaria, regeneration, endocannabinoid
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Straiker, Alex, and Jane M. Sullivan. "Cannabinoid Receptor Activation Differentially Modulates Ion Channels in Photoreceptors of the Tiger Salamander." Journal of Neurophysiology 89, no. 5 (May 1, 2003): 2647–54. http://dx.doi.org/10.1152/jn.00268.2002.
Full textAbstract:
Cannabinoid CB1 receptors have been detected in retinas of numerous species, with prominent labeling in photoreceptor terminals of the chick and monkey. CB1 labeling is well-conserved across species, suggesting that CB1 receptors might also be present in photoreceptors of the tiger salamander. Synaptic transmission in vertebrate photoreceptors is mediated by L-type calcium currents—currents that are modulated by CB1 receptors in bipolar cells of the tiger salamander. Presence of CB1 receptors in photoreceptor terminals would therefore be consistent with presynaptic modulation of synaptic transmission, a role seen for cannabinoids in other parts of the brain. Here we report immunohistochemical and electrophysiological evidence for the presence of functional CB1 receptors in rod and cone photoreceptors of the tiger salamander. The cannabinoid receptor agonist WIN 55212-2 enhances calcium currents of rod photoreceptors by 39% but decreases calcium currents of large single cones by 50%. In addition, WIN 55212-2 suppresses potassium currents of rods and large single cones by 44 and 48%, respectively. Thus functional CB1 receptors, present in the terminals of rod and cone photoreceptors, differentially modulate calcium and potassium currents in rods and large single cones. CB1 receptors are therefore well positioned to modulate neurotransmitter release at the first synapse of the visual system.
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Ghosh, Sharmistha, Ramesh K. Ganju, and Jerome E. Groopman. "Cannabinoids Inhibit the CXCL12-Induced Migration of T Lymphocytes." Blood 104, no. 11 (November 16, 2004): 2667. http://dx.doi.org/10.1182/blood.v104.11.2667.2667.
Full textAbstract:
Abstract Cannabinoids are both exogenous compounds produced by Cannabis sativa, known for their psychoactive properties, and a family of related endogenous ligands whose functions have been recently characterized. The reported effects of cannabinoids on the immune system include inhibition of T lymphocyte proliferation, altered production of cytokines by T helper cells and decreased antibody formation by B cells. Cannabinoid receptors have been detected in several immune cells, including monocytes, macrophages, basophils and B and T lymphocytes. CB2 (Cannabinoid Receptor 2) appears to be the predominant cannabinoid receptor in the immune system, while the CB1 receptor is found primarily in the brain. We observed high levels of CB2 expression in the Jurkat T lymphocyte cell line, while others have reported expression of the CB2 receptor in CD8+ T lymphocytes. Here, we studied the ability of synthetic and endogenous cannabinoids to modulate a key function of T lymphocytes: chemotactic migration in response to the chemokine CXCL12 (also known as stromal cell-derived factor-1). We observed a 40–50% inhibition of CXCL12-induced chemotaxis in Jurkat T cells with the endogenous cannabinoid anandamide (at 15 μM concentration) and with the synthetic cannabinoids CP55,940 and Win-55,212–2 (each at 10 μM concentration). Inhibition occurred in a dose-dependent manner, indicating that it is a regulated, receptor-mediated process. Further studies showed that the inhibition of migration involved, in part, significant down-regulation of the CXCL12 receptor, CXCR4. We are currently elucidating the signaling cascade whereby endogenous cannabinoids may limit T cell migration in response to CXCL12. Thus, cannabinoids may be novel mediators of immunosuppression when clinically desired.
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Vieira, Graziela, Juliana Cavalli, Elaine C. D. Gonçalves, Saulo F. P. Braga, Rafaela S. Ferreira, Adair R. S. Santos, Maíra Cola, Nádia R. B. Raposo, Raffaele Capasso, and Rafael C. Dutra. "Antidepressant-Like Effect of Terpineol in an Inflammatory Model of Depression: Involvement of the Cannabinoid System and D2 Dopamine Receptor." Biomolecules 10, no. 5 (May 20, 2020): 792. http://dx.doi.org/10.3390/biom10050792.
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Depression has a multifactorial etiology that arises from environmental, psychological, genetic, and biological factors. Environmental stress and genetic factors acting through immunological and endocrine responses generate structural and functional changes in the brain, inducing neurogenesis and neurotransmission dysfunction. Terpineol, monoterpenoid alcohol, has shown immunomodulatory and neuroprotective effects, but there is no report about its antidepressant potential. Herein, we used a single lipopolysaccharide (LPS) injection to induce a depressive-like effect in the tail suspension test (TST) and the splash test (ST) for a preventive and therapeutic experimental schedule. Furthermore, we investigated the antidepressant-like mechanism of action of terpineol while using molecular and pharmacological approaches. Terpineol showed a coherent predicted binding mode mainly against CB1 and CB2 receptors and also against the D2 receptor during docking modeling analyses. The acute administration of terpineol produced the antidepressant-like effect, since it significantly reduced the immobility time in TST (100–200 mg/kg, p.o.) as compared to the control group. Moreover, terpineol showed an antidepressant-like effect in the preventive treatment that was blocked by a nonselective dopaminergic receptor antagonist (haloperidol), a selective dopamine D2 receptor antagonist (sulpiride), a selective CB1 cannabinoid receptor antagonist/inverse agonist (AM281), and a potent and selective CB2 cannabinoid receptor inverse agonist (AM630), but it was not blocked by a nonselective adenosine receptor antagonist (caffeine) or a β-adrenoceptor antagonist (propranolol). In summary, molecular docking suggests that CB1 and CB2 receptors are the most promising targets of terpineol action. Our data showed terpineol antidepressant-like modulation by CB1 and CB2 cannabinoid receptors and D2-dopaminergic receptors to further corroborate our molecular evidence.
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Vieira-Coelho, M., J. Azevedo, and M. Esteves. "New Potential Molecular Targets for Cannabis Addition." European Psychiatry 24, S1 (January 2009): 1. http://dx.doi.org/10.1016/s0924-9338(09)70703-5.
Full textAbstract:
Cannabis is considerer the most widely abused illicit drug in the world. The recent rising prevalence of cannabis use by young adults and increasing evidence of adverse health effects makes the search for new pharmacotherapy to reduce cannabis abuse extremely important. To date no medication has been approved for the treatment of cannabis addition.This study reviews recent results with potential interest for future pharmacological treatment of Cannabis dependence. Most of the relevant data obtained for treatment of cannabis dependence target the endocannabinoid or the central cholinergic systems, both involved and interact in brain systems implicated drug reinforcement. In laboratory animals blockade of cannabinoids CB1 receptors reverses central effects of cannabinoids. Rimonabant is a selective, orally active, cannabinoid CB1 receptor antagonist (inverse agonist) that has been shown in animals to modulate cannabinoid signaling in brain reward circuit. In humans, it has been shown that rimonabant, single or repeated oral doses blocked psychological and physiological effects of smoked marijuana (1). Although psychiatric adverse side affects like depression were reported with rimonabant, this compound was already been approved for treatment of obesity and metabolic syndrome. Very recently, blockade of α7 nicotinic receptors was shown to reverse abuse-related behavioral and neurochemical effects of cannabinoids in rats (2).In conclusion, besides cannabinoid CB1 receptor, the homomeric α7 nicotinic receptors are novel molecular targets in the development of new drugs for treatment of cannabis addition.
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Piszcz, Jaroslaw A., Miroslawa Pietruczuk, Janusz S. Kloczko, Milena Dabrowska, Marzenna Galar, and Marek P. Milewski. "Expression of Cannabinoid Receptors on the Neoplastic Lymphocytes in Patients with Chronic Lymphocytic Leukemia." Blood 104, no. 11 (November 16, 2004): 4804. http://dx.doi.org/10.1182/blood.v104.11.4804.4804.
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Abstract Endocannabinoids take part in the physiology of neural and immune systems. The latest data showed that these compounds and their receptors play an important role in proliferation and apoptosis of various neoplastic cells. Cannabinoids were shown to increase apoptosis in human leukemia and lymphoma cell lines and culture of neoplastic cells obtained from patients with T-cell acute lymphoblastic leukemia. The aim of the study was an assessment of cannabinoid receptors expression on lymphocytes B derived from patients with CLL. The study group contains newly diagnosed, untreated adult patients with B-cell chronic lymphocytic leukemia; 13 male and 7 female, aged from 44 to 65. All of the patients were in B or C stage according to Binet. Peripheral blood samples from 10 healthy adult donors were used as the control group. The patients were hospitalized in the Department of Haematology, Medical University in Bialystok, Poland. Diagnosis of CLL in all cases was confirmed by routine immunophenotyping study. For flow cytometric analysis 1x105 – 1x106 of peripheral blood cells were incubated with 10ul of anty CB1 and anty CB2 polyclonal antibodies (American Diagnostics). Then 10ul of monoclonal antibodies IgG1-FITC and CD19-PE (Becton Dickinson) were added and the samples were incubated for 20 min in dark in 4°C. The samples were lysed, fixed and stabilized using Immuno-Prep (Coulter procedure) and assessed by flaw cytometry (Epics XL, Coulter). Statistical analysis was performed using non parametric U Mann-Whitney and Wilcoxon Tests. The conducted study revealed high expression of CB1 and CB2 receptors on the surface of neoplastic lymphocytes. The percentage of CB1/CD19 and CB2/CD19 positive cells in CLL patients were significantly higher, compared to the control group respectively (81.2±9,8% vs 12.0±9,3% p<0,05; 94,8±11,0 % vs 9,9±4,0%, p<0,05). No difference was noticed between the percentage of lymphocytes with CB1 and CB2 receptors expression in CLL and control group. Fluorescent intensity of CB2 receptors was about ten folds higher than CB1 receptors in both groups. The study demonstrated the presence of both types of cannabinoid receptors (CB1 and CB2) on neoplastic cells derived from patients with chronic lymphocytic leukemia. The higher percentage of B-lymphocytes expressing cannabinoid receptors in CLL patient suggests that the cannabinoid system may take part in CLL development. High intensity of CB2 receptor may be another target in CLL treatment.
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Wang, Ze-Jun, Sherry Shu-Jung Hu, Heather B. Bradshaw, Liqin Sun, Ken Mackie, Alex Straiker, and Thomas Heinbockel. "Cannabinoid receptor-mediated modulation of inhibitory inputs to mitral cells in the main olfactory bulb." Journal of Neurophysiology 122, no. 2 (August 1, 2019): 749–59. http://dx.doi.org/10.1152/jn.00100.2018.
Full textAbstract:
The endocannabinoid (eCB) signaling system has been functionally implicated in many brain regions. Our understanding of the role of cannabinoid receptor type 1 (CB1) in olfactory processing remains limited. Cannabinoid signaling is involved in regulating glomerular activity in the main olfactory bulb (MOB). However, the cannabinoid-related circuitry of inputs to mitral cells in the MOB has not been fully determined. Using anatomical and functional approaches we have explored this question. CB1 was present in periglomerular processes of a GAD65-positive subpopulation of interneurons but not in mitral cells. We detected eCBs in the mouse MOB as well as the expression of CB1 and other genes associated with cannabinoid signaling in the MOB. Patch-clamp electrophysiology demonstrated that CB1 agonists activated mitral cells and evoked an inward current, while CB1 antagonists reduced firing and evoked an outward current. CB1 effects on mitral cells were absent in subglomerular slices in which the olfactory nerve layer and glomerular layer were removed, suggesting the glomerular layer as the site of CB1 action. We previously observed that GABAergic periglomerular cells show the inverse response pattern to CB1 activation compared with mitral cells, suggesting that CB1 indirectly regulates mitral cell activity as a result of cellular activation of glomerular GABAergic processes . This hypothesis was supported by the finding that cannabinoids modulated synaptic transmission to mitral cells. We conclude that CB1 directly regulates GABAergic processes in the glomerular layer to control GABA release and, in turn, regulates mitral cell activity with potential effects on olfactory threshold and behavior. NEW & NOTEWORTHY Cannabinoid signaling with cannabinoid receptor type 1 (CB1) is involved in the regulation of glomerular activity in the main olfactory bulb (MOB). We detected endocannabinoids in the mouse MOB. CB1 was present in periglomerular processes of a GAD65-positive subpopulation of interneurons. CB1 agonists activated mitral cells. CB1 directly regulates GABAergic processes to control GABA release and, in turn, regulates mitral cell activity with potential effects on olfactory threshold and behavior.
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Michler, Thomas, Martin Storr, Johannes Kramer, Stefanie Ochs, Antje Malo, Simone Reu, Burkhard Göke, and Claus Schäfer. "Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms." American Journal of Physiology-Gastrointestinal and Liver Physiology 304, no. 2 (January 15, 2013): G181—G192. http://dx.doi.org/10.1152/ajpgi.00133.2012.
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The endocannabinoid system has been shown to mediate beneficial effects on gastrointestinal inflammation via cannabinoid receptors 1 (CB1) and 2 (CB2). These receptors have also been reported to activate the MAP kinases p38 and c-Jun NH2-terminal kinase (JNK), which are involved in early acinar events leading to acute pancreatitis and induction of proinflammatory cytokines. Our aim was to examine the role of cannabinoid receptor activation in an experimental model of acute pancreatitis and the potential involvement of MAP kinases. Cerulein pancreatitis was induced in wild-type, CB1−/−, and MK2−/− mice pretreated with selective cannabinoid receptor agonists or antagonists. Severity of pancreatitis was determined by serum amylase and IL-6 levels, intracellular activation of pancreatic trypsinogen, lung myeloperoxidase activity, pancreatic edema, and histological examinations. Pancreatic lysates were investigated by Western blotting using phospho-specific antibodies against p38 and JNK. Quantitative PCR data, Western blotting experiments, and immunohistochemistry clearly show that CB1 and CB2 are expressed in mouse pancreatic acini. During acute pancreatitis, an upregulation especially of CB2 on apoptotic cells occurred. The unselective CB1/CB2 agonist HU210 ameliorated pancreatitis in wild-type and CB1−/− mice, indicating that this effect is mediated by CB2. Furthermore, blockade of CB2, not CB1, with selective antagonists engraved pathology. Stimulation with a selective CB2 agonist attenuated acute pancreatitis and an increased activation of p38 was observed in the acini. With use of MK2−/− mice, it could be demonstrated that this attenuation is dependent on MK2. Hence, using the MK2−/− mouse model we reveal a novel CB2-activated and MAP kinase-dependent pathway that modulates cytokine expression and reduces pancreatic injury and affiliated complications.