Tesis: "Cannabinoid CB1 receptor"

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Smith, Tricia. "Effects of Cannabinoid Receptor Interacting Protein (CRIP1a) on Cannabinoid Receptor (CB1) Function." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1977.

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EFFECTS OF CANNABINOID RECEPTOR INTERACTING PROTEIN (CRIP1a) ON CANNABINOID (CB1) RECEPTOR FUNCTION. By Tricia Hardt Smith, B.S., M.S. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University Virginia Commonwealth University, 2009. Major Director: Dana E. Selley, Ph.D., Department of Pharmacology and Toxicology This dissertation examines modulation of cannabinoid CB1 receptor function by Cannabinoid Receptor Interacting Protein (CRIP1a), a novel protein that binds the C-terminus of CB1 receptors. In Human embryonic kidney cells expressing human CB1 receptors (hCB1-HEK) and hCB1-HEK cells stably co-expressing CRIP1a (hCB1-HEK-CRIP1a), quantitative immunoblotting revealed a CRIP1a/CB1 molar ratio of 5.4 and 0.37, respectively, with no difference in CB1 receptor expression. To test the hypothesis that CRIP1a modulates CB1 receptor signaling, G-protein and effector activity were examined with and without full, partial and inverse agonists. [35S]GTPgS binding, which measures G-protein-coupled receptor (GPCR)-mediated G-protein activation, showed that CRIP1a inhibited constitutive CB1 receptor activity, as indicated by the decreased effect of the inverse agonist SR141716A. CRIP1a also decreased CB1 receptor-mediated G-protein activation by high efficacy agonists, whereas moderate and low efficacy agonists were unaffected. In experiments varying Na+ concentration, CRIP1a decreased spontaneous G-protein activation at low Na+ concentrations, where spontaneous GPCR activity is highest. This effect was eliminated by pertussis toxin pre-treatment, indicating that CRIP1a only inhibits GPCR-mediated activity. To determine whether CRIP1a modulates receptor adaptation, hCB1-HEK (±CRIP1a) cells were pretreated with WIN or THC. Both ligands desensitized CB1 receptor-mediated G-protein activation, but desensitization was unaffected by CRIP1a. In contrast, CRIP1a attenuated downregulation of CB1 receptor binding sites by WIN, but not THC. Downstream, CRIP1a attenuated constitutive CB1 receptor-mediated inhibition of cAMP, as indicated by elimination of SR141716A-stimulated cAMP, without affecting agonist-induced cAMP inhibition. Constitutive inhibition was not due to endocannabinoids because LC-ESI-MS-MS did not detect endocannabinoids in hCB1-HEK (±CRIP1a) cells. To determine whether effects of CRIP1a were conserved among cell types, Chinese Hamster Ovary cells expressing CB1 receptors were stably co-transfected with CRIP1a, and had a CRIP1a/CB1 receptor molar ratio of 15 and 1900 with and without CRIP1a over-expression, respectively. In this model, CRIP1a inhibited constitutive CB1 receptor-mediated G-protein activity, but activation by agonists was enhanced, suggesting CRIP1a effects were dependent on stoichiometry of CRIP1a/CB1 receptor or cell type. Overall, these results indicate that CRIP1a decreases constitutive CB1 receptor activity, modulates agonist efficacy, and inhibits CB1 receptor downregulation, in a ligand- and cellular environment-dependent manner.

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2

Daigle, Tanya L. "Molecular mechanisms of CB1 cannabinoid receptor signaling and internalization /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/10527.

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3

Slaughter, Kimari. "Synthesis and Development of Potential CB1 Receptor Neutral Antagonists." ScholarWorks@UNO, 2012. http://scholarworks.uno.edu/td/1483.

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Cannabis and its derivatives have been used for both medicinal and recreational purposes. The study of this plant led to the discovery of over 60 cannabinoids, found exclusively in cannabis, that contribute to the behavioral effects of cannabis use, the most common is delta-9-tetrahydrocannabinol. Cannabinoid receptors function to increase activity in the mesolimbic dopamine reward system. Dopamine is a neurotransmitter that plays a major role in addition and its regulation plays a crucial role in mental and physical well-being. There is evidence that CB1 receptors are important to the reinforcing effects and the development of physical dependence on opiate drugs. Studies have shown that increased levels of dopamine are consistent with addiction while reduced levels lead to a decline in recreational use. The goal of this research is to design, synthesize and develop potential CB1 receptors that exhibit a neutral cannabinoid antagonist pharmacological profile.

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4

Horswill, James G. "Pharmacological characterisation of a novel cannabinoid CB1 receptor allosteric modulator." Thesis, University of Reading, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.541953.

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5

Grim, Travis. "Synthetic cannabinoids versus delta-9-tetrahydrocannabinol: abuse-related consequences of enhanced efficacy at the cannabinoid 1 receptor." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/4039.

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In the past ten years, synthetic cannabinoids (SC) have emerged as drugs of abuse. Unlike D9-tetrahydrocannabinol (THC), many SCs are associated with serious health complications and death. One way in which THC and SCs differ lies with their enhanced potency and efficacy at the CB1 receptor. No current methods exist to measure efficacy at the CB1 receptor in vivo, and the abuse-related properties of SC cannabinoids are not well explored. Here, we utilized CB1 wild type (WT), heterozygous (HET), and knockout (KO) mice. By employing CB1 ligands which differ in efficacy we have developed a method to explore the relationship between efficacy and the ability to produce cannabimimetic (catalepsy, hypothermia, and antinociception) effects when CB1 expression was reduced by half. Additionally, the intracranial self-stimulation procedure (ICSS) was utilized to investigate the effects of enhanced efficacy at CB1 upon reward processes using representative SC CP55,940. As predicted, the potency shift between WT and HET mice inversely correlated with the efficacy of the test drug for both hypothermia and antinociception, but not catalepsy. This efficacy stratification was correlated with the agonist-stimulated [35S]GTPgS binding assay, demonstrating this model as an effective tool to ascertain in vivo efficacy differences at CB1. In ICSS, CP55,940 elicited only rate-decreasing effects acutely, although tolerance developed following repeated dosing, with no evidence for spontaneous or rimonabant-precipitated withdrawal. Together, these data indicate that highly efficacious cannabinoid ligands require few receptors to produce cannabimimetic effects, and that the model provides an effective means to quickly ascertain differences in efficacy.

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6

Wing, Victoria Caroline. "The role of the cannabinoid CB1 receptor subtype in nicotine dependence." Thesis, University of Newcastle Upon Tyne, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500924.

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Tobacco smoking, considered an addiction to nicotine, is a worldwide health problem but limited effective pharmacotherapies are available. Nicotine acts on nicotinic acetylcholine receptors in the brain thus interacting with a range of neurotransmitter systems of which the mesocorticolimbic dopamine system is considered crucial for drug dependence. The endocannabinoid system has also been implicated in nicotine dependence and the cannabinoid CB1 receptor antagonist rimonabant has shown efficacy as a smoking cessation aid. This thesis aimed to further examine the role of CBl receptors in the motivational properties of nicotine, both positive and negative.

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Marcu, Jahan Phillip. "Novel Insights into CB1 Receptor Signaling and the Anabolic Role of Cannabinoid Receptors in Bone." Diss., Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/233543.

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Cell Biology Ph.D. Activation of the CB1 receptor is modulated by aspartate residue D2.63176 in transmembrane helix (TMH) II. Interestingly, D2.63 does not affect the affinity for ligand binding at the CB1 receptor. Studies in class A GPCRs have suggested an ionic interaction between residues of TMHII and VII. In this report, modeling studies identified residue K373, in the extracellular (EC)-3 loop, in charged interactions with D2.63. We investigated this possibility by performing reciprocal mutations and biochemical studies. D2.63176A, K373A, D2.63176A-K373A, and the reciprocal mutant with the interacting residues juxtaposed, D2.63176K-K373D were characterized using radioligand binding and guanosine 5'-3-O-(thio)triphosphate functional assays. None of the mutations resulted in a significant change in the binding affinity of CP55,940 or SR141716A. Computational results indicate that the D2.63176-K373 ionic interaction strongly influences the conformation(s) of the EC-3 loop, providing a structure-based rationale for the importance of the EC-3 loop to signal transduction in CB1. Specifically, the putative ionic interaction results in the EC-3 loop pulling over the top (extracellular side) of the receptor; this EC-3 loop conformation may serve protective and mechanistic roles. These results suggest that the ionic interaction between D2.63176 and K373 is crucial for CB1 signal transduction. This work may help to aide drug design efforts for the effective treatment of different diseases. The cannabinoid receptors of osteoblasts may represent a target for the treatment of bone disorders such as osteoporosis. Our research demonstrates that cannabinoids can affect important signaling molecules in osteoblasts. In MC3T3-E1 osteoblastic cells, the CB1 antagonist, AM251, has been reported to induce increases in Runx2 mRNA, mineralized bone nodule formation, and activation of signaling molecules such as ERK and AKT (Wu et al., 2011). Studies from our lab characterizing mice in which both CB1 and CB2 receptors were inactivated by homologous recombination have demonstrated increased bone mass coupled with enhanced osteoblast differentiation of bone marrow stromal cells in culture (manuscript in preparation). We explored the effect of antagonizing CB1 and CB2 cannabinoid receptors in osteoblastic cells to gain insights into molecular pathways that may help to explain the effects of the endocannabinoid system (ECS) in bone development. Our data was generated by running time course experiments with MC3T3-E1 cells under the influence of SR141716A, SR144528 or both in combination. The cells were harvested with a lysis buffer at specific time points and analyzed by western blot analysis. Quantification of protein activation was calculated using LiCor imaging equipment and software. Within 15 minutes, treatment with the CB1 receptor antagonist SR141716A resulted in several fold increases in pERK, pSMAD158, and pAKT. SR144528, a CB2 receptor antagonist, caused increases in pERK and pSMAD158, but not pAKT. When both antagonists were applied together, pERK and pSMAD158 levels increased, while pAKT signaling was diminished compared to SR141716A alone. The finding that cannabinoid receptor antagonists alter the activity of the SMAD158 complex is a novel finding, which suggests that cannabinoids can influence bone morphogenic signaling pathways, and therefore play a significant role in osteoblast differentiation and function. Temple University--Theses

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8

Feliszek, Monika [Verfasser]. "Age-dependent cannabinoid CB1 receptor plasticity and search for histamine H4 receptors in the brain / Monika Feliszek." Bonn : Universitäts- und Landesbibliothek Bonn, 2016. http://d-nb.info/1119888875/34.

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9

Jacob, Wolfgang. "Role of the Cannabinoid Receptor Type 1 (CB1) in Synaptic Plasticity, Memory and Emotionality." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-72307.

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10

Marsicano, Giovanni. "Physiological role of the cannabinoid receptor 1 (CB1) in the murine central nervous system." Thesis, Open University, 2001. http://oro.open.ac.uk/58198/.

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The cannabinoid system is involved in many functions of mammalian brain, such as learning and memory, pain perception and 'locomotion. The "brain type" cannabinoid receptor CB 1 is one of the key elements of the cannabinoid system. In this Thesis, some aspects of the neurobiology of mouse CB 1 are described. CB 1 mRNA distribution was analysed by single and double in situ hybridization (ISH), revealing the expression of the receptor in specific neuronal subpopulations. This expression pattern suggests many putative functional cross-talks between the cannabinoid system and other signalling molecules in the brain, such as glutamate, GABA, cholecystokinin and nitric oxide (NO). The putative functional interactions of the cannabinoid system with the NO pathway was studied by pharmacological treatment of neuronal NO synthase (nNOS) mutant mice with the CBI agonist A9-tetrahydrocannabinol (A9-THC). The results showed that nNOS is necessary for some central effects of A9-THC. Moreover, ISH analysis revealed. that nNOS-deficient mice contain levels of CBI lower than normal in selected brain regions. A "conditional" targeting approach was developed to gain insights into the specific functions of CB 1 in mouse brain. By gene targeting experiments, two mutant lines were obtained. The "Flox CB 1" mouse line, containing the whole open reading frame of CB I flanked by two loxP sites will be the key tool for the generation of mouse mutants with a spatiotemporal-restricted deletion of CB I. The "CBN" mice, carrying a "null" mutation of CB 1, were used for a study aimed to clarify some aspects of the in vitro neuroprotective activity of cannabinoids and, in particular, the involvement of CB 1. In vitro oxidative stress assays were performed on cell lines and on primary neuronal cultures derived from homozygous CBN/CBN mice and wild type littermates. The results indicate a differential protective activity of cannabinoids on cell lines and primary cultures. However, CBI does not appear to be involved in the in vitro leuroprotective effects of cannabinoids.

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11

Marsicano, Giovanni. "Physiological role of the cannabinoid receptor 1 (CB1) in the murine central nervous system." n.p, 2000. http://ethos.bl.uk/.

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12

Galera, López Lorena 1993. "Signalling mechanisms involved in memory function : focus on the effects of Δ9-tetrahydrocannabinol". Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2021. http://hdl.handle.net/10803/672693.

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Memory is a physiological brain function crucial for adaptive behaviour of individuals. Memory alterations are described as impairments in the processes by which memory is perceived, encoded, consolidated, retrieved, or used. there are countless situations that can lead to memory alterations. In this thesis we used specific murine mouse models to study the cellular and molecular mechanisms involved in learning and memory performance in specific situations where memory is compromised. Specifically, we described that repeated non-amnesic low doses of Δ9-tetrahydrocannabinol (THC) affect memory performance through serotonergic signalling in mice. Moreover, we reported specific memory alterations associated to the genetic inhibition of protein kinase C (PKC) gamma gene. Additionally, we revealed the involvement of the PKC-gamma isoform in the amnesic-like effects produced by THC in mice. Overall, combining behavioural, biochemical, and pharmacological approaches we have advanced in the understanding of relevant mechanisms for memory function and dysfunction associated to cannabis exposure. La memoria es una función fisiológica del cerebro cuyas alteraciones se definen como déficits en la percepción, codificación, consolidación, recuperación o utilización de esta. En esta tesis hemos utilizado modelos específicos de ratón para estudiar los mecanismos celulares y moleculares involucrados en el desempeño del aprendizaje y de la memoria cuando esta se encuentra afectada. Específicamente, describimos que dosis bajas repetidas y no amnésicas de Δ9-tetrahidrocannabinol (THC) afectan al funcionamiento de la memoria a través de la señalización serotoninérgica. Además, reportamos alteraciones de la memoria asociadas a la inhibición genética de la isoforma gamma de la proteína quinasa C (PKC). Por otra parte, mostramos la participación de la isoforma PKC-gamma en los efectos de tipo amnésico producidos por el THC. Combinando enfoques conductuales, bioquímicos y farmacológicos, hemos avanzado en la comprensión de los mecanismos implicados en la función y la disfunción de la memoria asociada a la exposición al cannabis.

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13

Altomonte, Stefano. "Cannabinoid receptor subtype-1 (CB1) ligands : synthesis and brain PET imaging with 11C and 18F radiotracers." Thesis, University of Aberdeen, 2014. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=214832.

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14

Bajzer, Matej. "The Role of the Cannabinoid Receptor Type 1 in Energy Balance, Glucose Metabolism, and Thermogenesis." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367944745.

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15

Fournet, Steven P. "High Resolution X-ray Diffraction Analysis of CB1 Receptor Antagonists as a Means to Explore Binding Affinity." ScholarWorks@UNO, 2013. http://scholarworks.uno.edu/td/1737.

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Abstract Charge density studies have been conducted on ten CB1 cannabinoid receptor antagonists via high resolution x-ray crystallography. Bond critical point values and various other properties derived from these studies including the electrostatic potential were analyzed in correlation to the affinity of each compound with the CB1 receptor. Correlation/anti-correlation was found between several properties and Ki. The data was also interpreted by principal component analysis with three principal components accounting for 85% of the data variation. Data mining was limit due to the low sample count and the requirements set for the inclusion of correlated/anti-correlated variables left fewer variables to analyze. The model presented is left for future interpretation.

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Vrechi, Talita Aparecida de Moraes. "O potencial terapêutico de compostos canabinoides em um modelo in vitro de morte neuronal." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/42/42137/tde-11082016-090204/.

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A neurodegeneração é o resultado da destruição progressiva e irreversível dos neurônios no sistema nervoso central, apresentando causas desconhecidas e mecanismos patológicos não totalmente elucidados. Fatores como a idade, o aumento da formação de radicais livres e/ou estresse oxidativo, defeito no metabolismo energético, a inflamação e acúmulo de elementos neurotóxicos e de proteínas malformadas no lúmen do retículo endoplasmático (RE) contribuem para o desenvolvimento dos processos neurodegenerativos. O sistema canabinoide tem sido proposto como neuroprotetor em diversos modelos de neurodegeneração como hipóxia aguda e epilepsia, isquemia cerebral, lesão cerebral e modelos de estresse oxidativo. Assim, este trabalho teve como objetivo investigar o papel do sistema canabinoide em uma linhagem de neuroblastoma (Neuro 2a) submetida a condições de estresse oxidativo (H2O2), inflamação (LPS) e estresse do RE (tunicamicina), avaliando parâmetros de viabilidade celular e vias de sinalização envolvidas. Nossos resultados mostram que o agonista canabinoide ACEA foi capaz de proteger as células da morte celular causada pela inflamação e pelo estresse de retículo endoplasmático, mas não pelo estresse oxidativo. Esse efeito neuroprotetor exercido pelo ACEA parece pelo menos em parte ocorrer via receptor CB1 no modelo de inflamação e ser independente deste receptor no modelo de estresse de RE. Os efeitos neuroprotetores observados envolveram a modulação dos níveis de proteínas pré-apoptóticas, CHOP e Caspase 12, e da proteína relacionada à sobrevivência celular ERK 1/2. Nossos dados sugerem um papel neuroprotetor do sistema canabinoide em mecanismos relacionados aos processos neurodegenerativos e propõem a manipulação desse sistema como possível alvo terapêutico. Neurodegeneration is the result of progressive and irreversible destruction of neurons in the central nervous system, with unknown causes and pathological mechanisms not fully elucidated. Factors such as age, increased formation of free radicals and/or oxidative stress, defects in energetic metabolism, inflammation and accumulation of neurotoxic factors and misfolded proteins in the lumen of the endoplasmic reticulum (ER) contribute to the development of neurodegenerative processes. The cannabinoid system has been proposed as neuroprotector in several models of neurodegeneration such as acute hypoxia and epilepsy, cerebral ischaemia, brain injury and oxidative stress models. This work aimed to investigate the role of the cannabinoid system in a neuroblastoma line (Neuro 2a) submitted to oxidative stress (H2O2), inflammation (LPS) and ER stress (tunicamycin) conditions, assessing cell viability parameters and signaling pathways involved. Our results show that the ACEA cannabinoid agonist was able to protect cells from cell death caused by inflammation and ER stress, but not from oxidative stress. This neuroprotective effect exerted by ACEA appears to occur at least in part via the CB1 receptor in inflammation model and it seems to be independent of this receptor in the ER stress model. The neuroprotective effects observed involved the modulation of the levels of pre-apoptotic proteins CHOP and Caspase 12 and the cell survival related protein ERK 1/2. Our data suggest a neuroprotective role of the cannabinoid system in mechanisms related to neurodegenerative processes and propose it as possible therapeutic target.

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17

Zehr, Bradley Preston. "Cannabinoid receptor 1 (CB1) agonist arachidonyl-2'-chloroethylamide (ACEA) induces Egr1 in murine 3T3-L1 and human adipocytes." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12255.

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Thesis (M.A.)--Boston University Obesity and type 2 diabetes mellitus are parallel global pandemics fueled by worldwide trends toward longer lifespan, Western high-fat diet, and sedentary lifestyle. Lipotoxicity – lipid overflow from adipose tissue to liver, muscle, and pancreas resulting from chronically elevated plasma free fatty acid levels – is now known to be the underlying cause of insulin resistance and T2DM. Control of lipolysis in adipose tissue is central to the regulation of plasma free fatty acid. Adipose triglyceride lipase (ATGL), the rate-limiting lipolytic enzyme in adipose tissue, is downregulated in the insulin-stimulated state, and this antilipolytic signal is defective in obesity and T2DM and may contribute to lipotoxicity. The antilipolytic insulin signal is mediated by mammalian target of rapamycin complex 1 (mTORC1), but how activated mTORC1 decreased ATGL expression remained elusive. The Kandror Lab recently identified transcription factor early growth responsive gene 1 (Egr1) as the missing link between insulin-activated mTORC1 and decreased ATGL expression. mTORC1 induces Egr1, which directly binds the ATGL promoter and decreases its expression. Intriguingly, Egr1 has also been implicated in a new model of the pathogenesis of insulin resistance in the pre-diabetic hyperinsulinemic state. Several groups have demonstrated that chronic hyperinsulinism causes an imbalance between PI3K/Akt signaling and MAPK signaling, and this defect is mediated by high levels of Egr1 in obesity. Additionally, the endocannabinoid system (ECS) is known to be hyperactive in obesity and diabetes, and antagonism of cannabinoid receptor 1 (CB1) by pharmaceutical rimonabant was effective at decreasing weight and improving insulin resistance in overweight and obese patients. Previous research demonstrated induction of Egr1 by CB1 stimulation in neurons, however the same effect has not been demonstrated in adipocytes. We stimulated murine 3T3-L1 and human adipocytes with 2 uM arachidonyl-2'-chloroethylamide (ACEA), a synthetic analogue of major endocannabinoid anandamide and a specific CB1 agonist. Egr1 mRNA was significantly increased in ACEA-stimulated murine and human adipocytes relative to controls after 4 hours, as analyzed by quantitative polymerase chain reaction. This finding potentially implicates hyperactive ECS during obesity in the pathogenesis of insulin resistance, and it further validates CB1 as a rich diabetes drug target.

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18

Häring, Martin [Verfasser]. "Cannabinoid CB1 receptor in the regulation of sociability, stress coping, and its interaction with the serotonergic system / Martin Häring." Mainz : Universitätsbibliothek Mainz, 2012. http://d-nb.info/1026397057/34.

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19

Schlosburg, Joel. "Differential roles of the two major endocannabinoid hydrolyzing enzymes in cannabinoid receptor tolerance and somatic withdrawal." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/2107.

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While there is currently active debate over possible therapeutic applications of marijuana and cannabis-based compounds, consistently their primary drawbacks have been the psychoactive properties, dependence, and abuse potential. Prolonged administration of ∆9-tetrahydrocannabinol (THC), the primary psychoactive constituent in marijuana, demonstrates both tolerance and physical withdrawal in both preclinical and clinical studies. Repeated THC administration also produces CB1 receptor adaptations in the form of reduced activation of receptors, along with a downregulation of membrane surface receptors, in many brain regions involved in THC-associated behaviors. The increased need for drug to maintain therapeutic effects, and a withdrawal syndrome following discontinuation of use, are common risk factors in drugs of abuse. Recently, compounds have been developed that prolong the availability of the major naturally occurring endogenous cannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), through inhibition of their catabolic breakdown by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The overall objectives of this research are to elucidate the physiologic roles of these two endogenous ligands and to determine if either can produce beneficial therapeutic effects without negative cannabis-like CNS effects. Therefore, we tested the impact of acute and prolonged blockade of FAAH and MAGL on a variety of cannabinoid-mediated behaviors and on precipitated cannabinoid withdrawal. Despite that acute blockade of FAAH and MAGL produce similar efficacy in reducing nociceptive responses, and both can reduce THC-induced somatic withdrawal, sustained blockade of these enzymes leads to remarkably different adaptations in CB1 receptor functioning. Namely, prolonged elevations in brain 2-AG leads to marked antinociceptive tolerance, cross-tolerance to exogenous cannabinoid agonists, and physical dependence. In contrast, sustained elevations in brain anandamide continues to dampen pain responses without apparent signs of physical withdrawal, loss of CB1 receptor activation as measured by [35S]GTPγS, or receptor downregulation as measured by [3H]CP,55940. These results suggest that chronic 2-AG elicits greater compensatory changes in CB1 receptor functions than anandamide. With similar efficacy in most therapeutic endpoints tested, and evidence of reduced impact on long-term function of the endocannabinoid system, these results distinguish FAAH as a more promising therapeutic target to treat pain and other conditions than MAGL.

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La, Porta Carmen 1985. "Involvement of the endocannabinoid system in osteoarthritis pain." Doctoral thesis, Universitat Pompeu Fabra, 2015. http://hdl.handle.net/10803/398384.

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Chronic pain is a major clinical problem producing huge economic and social burdens. Currently, chronic pain treatment has limited efficacy and significant side effects. One of the reasons of this unmet clinical need is the insufficient knowledge of the exact mechanisms involved in the generation and maintenance of chronic pain and pain-related comorbidities, such as affective and cognitive disorders that can negatively affect the life quality of patients. It is an important challenge to treat not only the nociceptive symptoms, but also the comorbidities accompanying chronic pain. In the present Thesis, we have validated different behavioral outcomes to evaluate the nociceptive, affective and cognitive alterations promoted by chronic pain in mice. Our work mainly focuses on a particular type of chronic pain that is the osteoarthritis pain. Pain is the principal symptom of osteoarthritis, a degenerative joint disease characterized by articular cartilage degradation. The endocannabinoid system has recently emerged as a new potential therapeutic target for osteoarthritis pain. The endocannabinoid system regulates a wide range of physiopathological processes including articular metabolism, pain, emotions and cognitive functions, and a therapeutic intervention on this system could offer the potential advantage to treat multiple aspects of this disease. We have used behavioral, genetic, pharmacological and biochemical approaches to study the involvement of the endocannabinoid system in different osteoarthritis pain-related alterations in mice, and explored the potential usefulness of the endocannabinoid system components as biomarkers for human osteoarthritis. El dolor crónico es un problema clínico grave con una enorme carga económica y social. Actualmente, el tratamiento del dolor crónico presenta eficacia limitada y efectos adversos significativos. Una de las razones de esta necesidad clínica insatisfecha es el escaso conocimiento de los mecanismos exactos que están involucrados en la generación y mantenimiento del dolor crónico y las comorbilidades relacionadas con el dolor, como son los trastornos afectivos y cognitivos. Estos tienen un impacto negativo sobre la calidad de vida de los pacientes y pueden agravar ulteriormente la percepción del dolor. Por ello, tratar no solamente los síntomas nociceptivos sino también las cormorbilidades que acompañan el dolor crónico representa un reto importante. En la presente Tesis, hemos validado diferentes modelos conductuales para evaluar las alteraciones nociceptivas, afectivas y cognitivas inducidas por el dolor crónico en ratones. Nuestro trabajo se centra principalmente en un tipo concreto de dolor crónico, el dolor osteoartrítico. El dolor es el principal síntoma de la osteoartritis, una enfermedad degenerativa de las articulaciones caracterizada por la degradación del cartílago. El sistema endocannabinoide ha emergido recientemente como una nueva diana terapéutica para el dolor osteoartrítico. Este sistema endógeno regula una vasta gama de procesos fisiopatológicos, incluyendo el metabolismo articular, el dolor y las funciones emocionales y cognitivas, y una intervención terapéutica sobre este sistema podría ofrecer la ventaja potencial de tratar diferentes aspectos relacionados con esta enfermedad. La combinación de aproximaciones comportamentales, genéticas, farmacológicas y bioquímicas nos han permitido determinar la participación de determinados componentes del sistema endocannabinoide en las diferentes alteraciones relacionadas con el dolor osteoartrítico en ratones. Además, hemos analizado la utilidad potencial de los componentes del sistema endocannabinoide como biomarcadores de la osteoartritis humana.

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21

Bouwer, Adoree. "An in Vitro investigation of the effects of Rimonabant (a cannabinoid CB1 receptor antagonist) on cell adhesion and inflammatory associated cytokine production." Diss., University of Pretoria, 2012. http://hdl.handle.net/2263/24508.

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There is good pharmacological evidence that cannabinoids caused cellular changes by interacting with specific cannabinoid receptors (CBR) (Klein et al., 2000). To date, two CBRs have been identified in the human body, designated Cannabinoid Receptor 1 (CB1) and Cannabinoid Receptor 2 (CB2) (Begg et al., 2005). Endogenously occurring compounds with action at the CBRs also exist and they are called endocannabinoids. One of the four known endocannabinoids is anandamide (AEA). The endocannabinoid system, present in the human body, plays a significant role in altering the physiology of the immune system. Enhancement of this system’s anti-inflammatory effect could possibly present a vital therapeutic target for central and peripheral inflammatory disorders. A number of synthetic CB1 or CB2 specific antagonists have been developed including the highly specific CB1 receptor antagonist/reverse agonist named Rimonabant/ SR141716A. SR compounds are considered unique because these compounds not only inhibit the binding and function of cannabimimetic agents, but also act as inverse agonists. Activation of CB1 receptors produces inappropriate CNS side effects including psychoactivity, dependence and sedation (Clayton et al., 2002) whereas CB1 receptor antagonists/inverse agonists avoid or prevent these side effects. Taking the above information into consideration, Rimonabant has the potential to offer an effective long term treatment of chronic inflammatory disorders without the serious side effects of commonly used treatments. The main aim of this study is to investigate the in vitro effects of Rimonabant alone and in combination with anandamide on inflammatory associated cytokine production by human umbilical vein endothelial cells (HUVEC) and macrophage cultures. After careful consideration of the evidence stating that endothelial cells produce several important molecules vital to the inflammatory response of the body and the confirmation that CB1 receptor mRNA is generally present in endothelial cells, the use of HUVEC was deemed to be satisfactory for this study. The first phase of the study was dedicated to establishing the technique to isolate HUVEC from fresh human umbilical cord within the local laboratory and to maintain these in culture for further use during experimental procedures to test the effects of CB1 ligands. The isolation procedure, trypsinising, freezing away and thawing methods used during this experiment produced healthy HUVEC in sufficient numbers for further use. The next step was to determine the maximum in vitro concentrations at which Rimonabant and anandamide had insignificant cytotoxic effect on selected human cells and in doing so, determine suitable concentrations for further experimentation. Both compounds had a dose related anti-proliferative response when tested on HUVEC. The same dose related response was observed during the Rimonabant exposure to human lymphocytes, but no decrease in lymphocyte viability was observed when treated with anandamide at the concentrations tested. It is evident from the results that there was an almost ten times difference in the IC50 value of the two different products (14.3 μM for Rimonabant and 124.2 μM for anandamide) which was statistically significant. Flow cytometry was used to determine the effects of Rimonabant and anandamide on the surface expression of the CR3 complement receptor by human neutrophils. Neither Rimonabant nor anandamide significantly affect CR3 expression on the surface of freshly isolated human neutrophils and would exclude the CR3 expression pathways as a potential mechanism of action for the anti-inflammatory effects of these compounds. The in vitro effect of Rimonabant and anandamide alone and in combination on the production of cytokines by human macrophages and by HUVEC was determined. Anandamide was shown to inhibit the production of all the detectable cytokines (IL-8, IL-1β and IL-6 in both cell types and IL-10 and TNF-α in macrophages). Furthermore this inhibitory effect was attenuated by pre-treatment Rimonabant. These results would suggest that anandamide could induce anti-inflammatory effects observed in macrophages and HUVEC, through cannabinoid receptors. Rimonabant also inhibited the production of all the detectable cytokines following treatment with 0.5 μM and 3 μM respectively. The anti-inflammatory effects of anandamide were attenuated when combined with 1 μM of Rimonabant. Throughout the various cytokine responses, the dose-response relationship appeared to follow a bell-shaped dose-response. This occurrence proposes that Rimonabant displaces anandamide and blocks the anti-inflammatory effects of the agonist. Flow cytometry was used to determine the effects of Rimonabant and anandamide alone and in combination on the extracellular surface expression of ICAM-1 by HUVEC. Neither Rimonabant nor anandamide had any significant inhibitory effect on the expression of ICAM-1 by HUVEC. Considering the low levels for ICAM-1 expressed by the HUVEC during this experiment and the literature supporting more effective methods of activating the ICAM-1 gene and subsequent up-regulation of ICAM-1 proteins, TNF-α stimulation of HUVEC might produce a different result compared to IL-1β stimulation. The final phase of the project was to determine the effects of Rimonabant and anandamide on the adhesion of human neutrophils to HUVEC. There was no significant difference with relation to the neutrophil adhesion to HUVEC following the treatment with various combination concentrations of the compounds, and also no significant effect following treatment with either test compound individually. Although a specific mechanism of action for Rimonabant could not be uncovered during this study, there is evidence that several possible mechanisms can be excluded. The results support observations made by other researchers and the hypothesis that Rimonabant has anti-inflammatory effects. The results provide motivation for further experimentation to better understand these anti-inflammatory actions of Rimonabant. Dissertation (MSc)--University of Pretoria, 2012. Pharmacology unrestricted

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22

SOFFIA, SILVIA. "Agonists of the Cannabinoid Receptor Type 1 (CB1) Promote Rat Cerebellar Neural Progenitor Cell Proliferation Through Activation of ERK and Akt Pathways." Doctoral thesis, Università degli studi di Padova, 2010. http://hdl.handle.net/11577/3421532.

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Endocannabinoids represent a novel class of intercellular messengers, the function of which includes retrograde signaling in the brain and mediation or modulation of several types of synaptic plasticity. Endocannabinoid signaling not only regulates the proliferation, migration, specification, survival, and phenotypic differentiation of neural progenitors during central nervous development (Harkany,T. et al., 2008) but has been shown to control proliferation and differentiation of neural stem/progenitor cells in the hippocampal subgranular zone and in the subventricular zone of the adult mammalian brain (Jiang,W. et al., 2005; Palazuelos,J. et al., 2006). To elucidate the cellular and molecular mechanisms underlying cannabinoid neurogenic action, we used neural progenitor cells isolated from primary cultures of rat postnatal cerebellum as an in vitro model of neural cell proliferation. These cells share some of the phenotypic and genotypic properties of stem cells, as characterized by immunocytochemistry and reverse transcription-polymerase chain reaction, respectively (Zusso,M. et al., 2004). The functional presence of the two cannabinoid receptors CB1 and CB2 in cerebellar neural progenitor cells at 10 days in vitro (DIV) was assessed by immunocytochemistry and Western blotting. Proliferation was evaluated using a [3H]-thymidine incorporation assay. A significant increase in cerebellar neural progenitor cell proliferation vs the corresponding vehicle control was found following 24 h incubation with the synthetic non-selective CBR agonists WIN 55,212-2 (100 nM) or CP 55,940 (1000 nM) (43 ± 22 % and 37 ± 8 %, respectively), which was completely abolished by treatment with 1000 nM AM 251 (1 h pre-incubation), a selective CB1 receptor antagonist. To evaluate a direct involvement of the CB1 receptor in the proliferative response, cerebellar neural progenitors were incubated for 24 h with ACEA (1-1000 nM), a potent selective CB1 receptor agonist. ACEA (1 nM and 10 nM) significantly increased [3H]-thymidine incorporation (by 50.59 ± 6.72 % and 35.77 ± 4.48 %, respectively) and this effect was completely reverted by 10 nM AM 251. To investigate the involvement of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK)1,2 and phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3-β signaling pathways in CB1 receptor-induced cerebellar neural progenitor proliferation, we performed SDS-PAGE Western blotting. Fifteen minutes incubation of cerebellar neural progenitor cells with 1 nM ACEA produced a significant activation of Akt (36.54 ± 7.21%) that persisted up to 30 min (21 ± 5 %). A significant, concomitant ERK1,2 activation (32 ± 4 %) was observed at this time, as well. A 1 h pre-incubation with 10 nM AM 251 per se did not affect Akt and MAPK phosphorylation levels but did inhibit the ACEA agonistic effect on both kinases. The existence of cross-talk between the two pathways was confirmed by using the corresponding selective inhibitors, LY294002 (75 µM, 3 h pre-incubation) and U0126 (10 µM, 1 h pre-incubation). The phosphatidylinositol 3-kinase inhibitor LY294002 not only inhibited 1 nM ACEA-induced cerebellar neural progenitor Akt activation but also ERK phosphorylation, while the mitogen-activated protein kinase kinase inhibitor U0126 inhibited ERK activation without affecting the Akt pathway, both in untreated and ACEA-treated cells. Preliminary experiments have been performed to investigate the potential role of ACEA in cerebellar neural progenitor cell differentiation, evaluating the expression pattern of the transcript variants of the ARE-binding protein AUF1, which is regulated during postnatal cerebellar development (Hambardzumyan,D. et al., 2009). Gli endocannabinoidi rappresentano una nuova classe di messaggeri intercellulari che mediano la conduzione retrograda del segnale sinaptico e regolano così varie forme di plasticità sinaptica. Il segnale endocannabinoide non solo controlla la proliferazione cellulare, la migrazione, il destino decisionale, la sopravvivenza, ed il differenziamento ad un fenotipo maturo dei progenitori neurali durante lo sviluppo del sistema nervoso centrale (Harkany,T. et al., 2008), ma è stato dimostrato possedere un ruolo nella proliferazione e nel differenziamento di cellule staminali/progenitrici neurali esistenti nella zona subgranulare di ippocampo e nella zona subventricolare del cervello di mammifero adulto (Jiang,W. et al., 2005; Palazuelos,J. et al., 2006). Allo scopo di definire i meccanismicellulari e molecolari che sottendono all’azione neurogenica di questi composti, è stato utilizzato un modello di proliferazione cellulare neurale in vitro rappresentato da cellule progenitrici neurali isolate da colture primarie di cervelletto di ratto postnatale. La caratterizzazione di queste cellule, sia genotipica, tramite RT-PCR, che fenotipica, tramite analisi immunocitochimica, ha evidenziato che esse possiedono proprietà tipiche delle cellule staminali (Zusso,M. et al., 2004). La presenza funzionale dei due recettori cannabici CB1 e CB2 nelle cellule progenitrici neurali cerebellari a 10 giorni in coltura (10 days in vitro, DIV) è stata confermata tramite analisi immunocitochimica e Western blotting. La proliferazione cellulare è stata valutata tramite saggio d’incorporazione di timidina triziata. Tramite questo saggio è stato riscontrato un aumento significativo rispetto al controllo della proliferazione dei progenitori neurali cerebellari, per trattamento di 24 ore con gli agonisti sintetici non selettivi dei recettori cannabici, WIN 55,212-2 (100 nM) o CP 55,940 (1000 nM) (43 ± 22 % e 37 ± 8 %, rispettivamente), completamente inibito dal pretrattamento di un’ora con l’antagonista selettivo del recettore CB1 AM 251 (1000 nM). Al fine di valutare il diretto coinvolgimento del recettore CB1 nella risposta proliferativa, le cellule progenitrici neurali cerebellari sono state incubate per 24 ore con ACEA, potente agonista selettivo del recettore CB1. ACEA, alla concentrazione di 1 e 10 nM, ha indotto una significativa incorporazione del radionuclide rispetto alle cellule non trattate (50.59 ± 6.72 % e 35.77 ± 4.48 %, rispettivamente), ma la risposta è stata completamente inibita da AM 251 allaconcentrazione 10 nM. Allo scopo di studiare il coinvolgimento delle cascate di trasduzione del segnale MEK/ERK1,2 ed IP3K/Akt/GSK3-β nella risposta proliferativa delle cellule progenitrici mediata dall’attivazione del recettore CB1, è stata usata la tecnica del SDS-PAGE Western blotting. L’incubazione delle cellule progenitrici con 1 nM ACEA ha prodotto un incremento significativo dei livelli di attivazione di Akt a 15 minuti (36.54 ± 7.21%) che persiste fino a 30 minuti di trattamento (21 ± 5 %), tempo a cui si registra un concomitante aumento dei livelli di fosforilazione della proteina ERK (32 ± 4 %). Il trattamento di 60 minuti con AM 251 alla concentrazione 10 nM non influenza i livelli basali di attivazione delle due chinasi, ma inibisce completamente l’effetto mediato da ACEA. Successivamente è stato possibile confermare l’esistenza di un "cross-talk" tra le due cascate di trasduzione del segnale tramite impiego dei rispettivi inibitori selettivi. L’inibitore della fosfatidilinositolo-3 chinasi, LY294002 (75 µM, 3 ore di preincubazione), ha inibito l’attivazione di entrambe le chinasi nelle cellule progenitrici trattate con ACEA, mentre l’inibitore di MEK, U0126 (10 µM, un’ora di preincubazione), ha inibito l’attivazione di ERK in cellule trattate e non, senza influenzare la fosforilazione di Akt. Sono stati eseguiti alcuni esperimenti preliminari per valutare un potenziale ruolo di ACEA nel differenziamento delle cellule progenitrici neurali cerebellari, tramite analisi dell’espressione delle varianti trascrizionali della proteina AUF1 che lega sequenze ricche di adenina e uracile dell’RNA messaggero ed è regolata durante lo sviluppo cerebellare postnatale (Hambardzumyan,D. et al., 2009).

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23

Soria, Rodríguez Guadalupe. "Sistemas cannabinoide y purinérgico: posibles sustratos neurobiológicos de la drogadicción." Doctoral thesis, Universitat Pompeu Fabra, 2006. http://hdl.handle.net/10803/7101.

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La adicción es un trastorno crónico de la conducta caracterizado por la búsqueda y el consumo compulsivos de la droga, la pérdida de control para limitar dicho consumo, a aparición de un estado emocional negativo cuando el acceso a la droga está impedido y la recaída en el proceso incluso tras largos períodos de abstinencia. El sistema dopaminérgico mesolímbico cortical ha sido propuesto como la principal base neurobiológica de la adicción, sin embargo existen otros sistemas de neurotransmision que participan en la consolidación del proceso adictivo. El sistema endocannabinoide, a traves del receptor CB1, participa en las propiedades adictivas de diferentes drogas de abuso como el delta9-tetrahidrocannabinol, la nicotina y la morfina. Sin embargo, hasta el momento de iniciar este trabajo, pocos estudios han demostrado una clara implicación del sistema endocannabinoide en las propiedades reforzantes de los psicoestimulantes. Mediante el uso de ratones CB1 knockout, hemos demostrado que el receptor CB1 participa en la eficacia reforzante de la cocaína. Además, la presencia de dicho receptor es necesaria para los procesos de consolidación de una conducta operante mantenida por la autoadministración de cocaína. Este estudio demuestra la importancia de dicho receptor CB1 en las propiedades adictivas de la cocaína, confirmando que el sistema endocannabinoide es un sustrato común para la adicción de drogas de abuso. Por otra parte, el sistema purinérgico modula numerosos sistemas de neurotransmisión en el SNC. La estrecha relación a nivel celular y funcional entre los receptores de adenosina y los receptores dopaminérgicos proporciona evidencias de que el sistema purinérgico podría modular los sistemas de recompensa. Utilizando diferentes modelos animales, hemos demostrado que los receptores de adenosina A2A son necesarios para que las propiedades adictivas de las drogas de abuso como los cannabinoides, los opioides, la nicotina y los psicoestimulantes se produzcan de un modo completo. Nuestros estudios nos permiten afirmar que ambos sistemas, el cannabinoide y el purinérgico podría suponer la existencia de nuevos sistemas de modulación común de los procesos adictivos. Asi, sería de gran interés desarrollar nuevas estrategias de bloqueo de los receptores A2A y CB1 para atenuar e incluso prevenir el desarrollo de la adicción. Drug addiction is a chronically relapsing disorder that is defined by a compulsion to take the drug intake, a loss of control in limiting intake and a withdrawal-negative affect state when the access to the drug is interrupted. Mesolimbic dopaminergic system has been proposed as a fundamental neurobiological substrate for drug addiction. However, there is evidence for other neurotransmitter systems involved in the consolidation of the addictive process. The endocannabinoid system, through the activation of CB1 receptor, participates in the addictive properties of different drugs of abuse such as delta9-tetrahydrocannabinol, morphine and nicotine. Nevertheless, few studies have revealed an important implication of CB1 receptor in the reinforcing properties of psychostimulants. By using CB1 knockout mice, we have demonstrated that CB1 receptor participates in the reinforcing efficacy of cocaine. Moreover, this receptor is necessary for the consolidation processes involved in cocaine maintained intravenous self-administration. Therefore, this study reveals an essential role of CB1 receptor in cocaine addictive properties, confirming that the endocannabinoid system is a common substrate of addiction to drugs of abuse. On the other hand, the purinergic system modulates different neurotransmitter systems in the CNS. Adenosine receptors are closely related to dopaminergic receptors at both cellular and functional levels, suggesting that purinergic system could modulate the reward systems. By using different animal models, we have demonstrated that A2A adenosine receptors are necessary for the development of the addictive properties of drugs of abuse such as opioids, cannabinoids, nicotine and cocaine. Our studies suggest that both cannabinoid and purinergic systems could represent new and common modulatory systems of addictive processes. Thus, it would be of interest to develop new therapeutic targets blocking CB1 and A2A receptors to attenuate the development of addiction.

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24

Busquets, Garcia Arnau 1985. "Targeting the endocannabinoid system for therapeutic purposes." Doctoral thesis, Universitat Pompeu Fabra, 2013. http://hdl.handle.net/10803/119617.

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The endocannabinoid system is an endogenous neuromodulatory system that regulates a plethora of physiological functions, including the modulation of memory, anxiety, pain, synaptic plasticity and neuronal excitability, among others. The activation of this system through exogenous or endogenous cannabinoid agonists has been proposed as a therapeutic strategy in different pathological states, although an important caveat to their use is the possible central adverse effects, such as memory impairment, anxiety and tolerance. The activity of the endocannabinoid system has been recently found involved in the pathophysiological conditions leading to obesity and fragile X syndrome, and the blockade of this system has also been investigated as a possible therapeutic approach. This thesis mainly focuses on the behavioral, paying more attention on the cognitive effects, cellular and molecular effects of exogenous and endogenous cannabinoids in order to identify potential therapeutic effects minimizing the negative consequences associated to the cannabinoid activation. This experimental research has been centered on the modulation of the positive and negative effects of Δ9-tetrahydrocannabinol, the main psychoactive component of the Cannabis sativa plant, the possibility to enhance the endogenous tone of specific endocannabinoids to improve certain therapeutic applications of cannabinoids, and the effects of inhibiting the endocannabinoid system in the amelioration of different traits associated to fragile X syndrome. The combination of behavioral, cellular and molecular approaches allowed the elucidation of different important aspects of the endocannabinoid system as an interesting therapeutic target. El sistema endocannabinoid és un sistema neuromodulador endogen que regula diferents funcions fisiològiques com la memòria, l’ansietat, el dolor i l’excitabilitat neuronal entre altres. L’activació d’aquest sistema per agonistes exògens o endògens ha estat usada com a estratègica terapèutica en diferents estats patològics tot i que els efectes adversos, com la pèrdua de memòria, l’ansietat o la tolerància, són el principal problema pel seu ús. El sistema endocannabinoid també s’ha trobat alterat en malalties com la obesitat o la síndrome del cromosoma X fràgil i, per tant, el bloqueig d’aquest sistema també s’ha emprat com a aproximació terapèutica. Aquesta tesis es centra en els efectes comportamentals i moleculars de l’administració exògena del Δ9-Tetrahydrocannabinol, el component principal de la planta Cannabis sativa, i en la modulació endògena del sitema endocannabinoid per tal de potenciar els efectes terapèutics minimitzant els efectes adversos dels cannabinoids. A més, en aquesta tesis també hem estudiat els posibles efectes terapèutics del bloqueig dels receptors cannabinoides en la síndrome del cromosoma X fràgil. La combinació d’aproximacions moleculars, farmacològiques, electrofisiològiques i comportamentals han permès el descobriment de diferents aspectes importants que permeten demostrar que el sistema endocannabinoid és una diana terapèutica molt interessant.

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25

Ghosh, Sudeshna. "Targeting the Endocannabinoid System to Reduce Inflammatory Pain." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/313.

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The endogenous cannabinoids (endocannabinoids) anandamide (AEA) and 2-arachidonylglycerol (2-AG) exert their effects predominantly through cannabinoid CB1 and CB2 receptors, but these actions are short-lived because of rapid hydrolysis by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Selective inhibition of either enzyme elevates CNS levels of the appropriate endocannabinoid and produces analgesic effects with fewer psychomimetic side effects than Δ9-tetrahydrocannabinol (THC), the primary active constituent of marijuana. While cannabinoid receptor agonists and FAAH inhibitors reliably produce anti-inflammatory and anti-hyperalgesic effects in the carrageenan test and other inflammatory pain models, much less is known about the consequences of inhibiting MAGL in these assays. Here, we tested whether the selective MAGL inhibitor JZL184 would reduce nociceptive behavior in the carrageenan test. JZL184 significantly attenuated carrageenan-induced paw edema and mechanical allodynia, whether administered before or after carrageenan. Complementary genetic and pharmacological approaches revealed that JZL184’s anti-allodynic effects required both CB1 and CB2 receptors, but only CB2 receptors mediated its anti-edematous actions. Importantly, the anti-edematous and anti-allodynic effects of JZL184 underwent tolerance following repeated injections of high dose JZL184 (16 or 40 mg/kg), but repeated administration of low dose JZL184 (4 mg/kg) retained efficacy. Interestingly, the anti-allodynic effects of the combination of low dose of JZL184 (4mg/kg) and high dose of the selective and long-acting FAAH inhibitor PF-3845 (10 mg/kg) was augmented compared with each drug alone. On the contrary, the combination treatment did not reduce edema more than either JZL184 or PR-3845 given alone. These results suggest that low doses of MAGL inhibitors alone or in combination with FAAH inhibitors, reduce inflammatory nociception through the activation of both CB1 and CB2 receptors with no evidence of tolerance following repeated administration.

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26

Sherwood, Alexander M. "Design, Synthesis and Biological Evaluation of Novel Compounds with CNS-Activity Targeting Cannabinoid and Biogenic Amine Receptors." ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1831.

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This work seeks to contribute to the discipline of neuropharmacology by way of structure activity relationship from the standpoint of an organic chemist. More specifically, we sought to develop robust synthetic methodology able to efficiently produce an array of compounds for the purpose of systematic evaluation of their interaction with specific sights within the central nervous system (CNS) in order to better understand the mind and to develop drugs that may have beneficial effects on neurological function. The focus of these studies has been toward the development of novel molecules, using a structure-activity relationship approach, that exhibit binding affinity at specific targets within the CNS. The merit of such studies is twofold: primarily, new compounds are produced that provide valuable scientific insight about their physiological targets, and secondarily, new synthetic methodologies that may arise in order to produce these compounds, thereby contributing to the whole of organic chemistry. As a result of the research described herein, the development of one high affinity and several moderate affinity compounds at the cannabinoid receptor subtype 1 (CB1) has been accomplished. The research demonstrates that a diaryl ether molecular scaffold represents a successful motif in the cannabinoid pharmacophore. The production of the compounds in the SAR studies also introduced a novel general synthetic methodology for the synthesis of diaryl ethers around a phloroglucinol core. A second project was initiated in order to explore the synthetic methods required to develop a general process for the synthesis of rigid aminobenzocyclobutane analogs of known phenethylamines with activity at monoaminergic neurotransmitter sites. Using the synthetic approach devised here, four novel aminobenzocyclobutane isomeric analogs of a known pharmacologically active phenethylamine, (RS)-phenylpropan-amine were synthesized and are currently being evaluated for pharmacological potential.

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27

Kerr, Jamie. "Allosteric modulation of the CB1 receptor." Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=196261.

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Bioactive compounds from Cannabis sativa have been used for millennia to alleviate the symptoms of a range of diseases. The physiological basis of effects such as analgesia, stimulation of hunger and reduction of inflammation was established in the late 20th century with the discovery of cannabinoid receptors but efforts to synthesise safe and potent drugs targeting these proteins have so far failed. The major barrier to research in this area is the instability of the receptors outside of biological settings, rendering elucidation of the binding sites by traditional means difficult. Certain small molecules can interact with the cannabinoid type 1 receptor (CB1) at locations distinct to the primary ligand docking site. Such allosteric modulation of the endocannabinoid system offers significant advantages over using orthosteric drugs and in this research a range of indole based structures were synthesised and tested in an attempt to improve the activity and drug-like nature of a lead compound. A partial structure-activity relationship was established, including the description of the most potent allosteric enhancer of CB1 so far reported. Efforts were also undertaken to investigate the allosteric binding environments using photoactivatable ligands based on a CB1 inhibitor. In combination with mutation studies and computer modelling this technique could allow the rational design of allosteric modulators, a task which is not trivial at present. Two photoactivatable compounds were synthesised and shown to interact with the receptor, with a method for isolating covalently labelled peptide fragments from other biomolecules demonstrated using “click chemistry” and a modified Wang resin. This work may find application in future investigations aiming to produce allosteric pharmaceuticals targeting CB1. Furthermore, the techniques described may be applied to study the binding site of a recently described allosteric endocannabinoid or could potentially be adapted to look at secondary binding domains in other G protein-coupled receptors.

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28

Aso, Pérez Ester. "Participación del sistema cannabinoide endógeno en el control de las respuestas relacionadas con trastornos afectivos." Doctoral thesis, Universitat Pompeu Fabra, 2008. http://hdl.handle.net/10803/7132.

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Los trastornos emocionales de tipo depresivo y la ansiedad son las formas más prevalentes de enfermedad mental y suponen un serio problema de salud en la sociedad occidental. Recientemente, se ha postulado que el sistema endocannabinoide pueda ser un importante sustrato en el desarrollo de estos trastornos dada su participación en el control de las emociones. Nuestros resultados demuestran que los animales carentes del receptor cannabinoide CB1 manifiestan un fenotipo de tipo depresivo asociado a una deficiencia del factor neurotrófico BDNF en el hipocampo, que podría estar causada por los elevados niveles de glucocorticoides liberados en respuesta al estrés en estos mutantes. Por otra parte, el sistema endocannabinoide participa en los efectos inducidos por la nicotina sobre la ansiedad y en la expresión del síndrome de abstinencia de esta droga. Así, la actividad del receptor CB1 alivia los efectos ansiogénicos de dosis elevadas de nicotina y facilita los efectos ansiolíticos de dosis bajas. Además, la administración del agonista cannabinoide 9-THC atenúa las manifestaciones somáticas y emocionales negativas de la abstinencia de nicotina. En general, considerando los resultados presentados en esta Tesis Doctoral, podemos afirmar que el receptor CB1 participa de forma determinante en la recuperación del balance homeostático del organismo tras la exposición a un estímulo emocional negativo, bien sea una situación estresante aguda o sostenida, o bien una droga que incrementa los niveles de ansiedad o cuya retirada produce abstinencia. Mood disorders such as depression and anxiety are the most common mental diseases and they suppose a serious health problem in our society. Recently, endocannabinoid system has been postulated to be an important substrate in the development of such disorders taking into account the role exerted by this neuromodulatory system in mood and emotions. Our results demonstrate that CB1 knockout mice exhibit a depressive-like phenotype associated to a deficiency in the neurotrophic factor BDNF in the hippocampus, which could be a consequence of the increased glucocorticoid release in response to stress exposure. On the other hand, the endocannabinoid system participates in nicotine induced effects on anxiety and in the expression of nicotine withdrawal. Thus, CB1 receptor activity attenuates anxiogenic-like effects and facilitates anxiolytic-like responses induced by high or low doses of nicotine, respectively. Moreover, 9-THC administration ameliorates somatic and negative motivational signs of nicotine withdrawal. In summary, the results presented in this Doctoral Thesis indicate that CB1 receptor participates in the recovery of the homeostatic balance after the exposure to negative emotional stimuli, either acute or sustained stress or a drug which induced anxiety-like effects or withdrawal signs after the end of the exposure.

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RUGGIERO, Emanuela. "Discovery of new CB2 cannabinoid receptor full agonists." Doctoral thesis, Università degli studi di Ferrara, 2014. http://hdl.handle.net/11392/2389407.

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Xiang, Guoqing. "Signaling Through Homomeric and Heteromeric Cannabinoid CB1 receptors." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5683.

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Cannabis (Marijuana) has multiple effects on the human body, such as analgesia, euphoria and memory impairment. Delta-9 tetrahydrocannabinol (D9-THC), the active ingredient in cannabis, binds to cannabinoid receptors, seven-transmembrane G protein-coupled receptors (GPCRs) that mediate a variety of physiological functions. GPCRs were believed to function only in homomeric forms, however, recent findings show that different GPCRs can also form heteromeric complexes that may expand their signaling properties. In this study, we focused on Cannabinoid CB1 receptor (CB1R) heteromers with the mu-opioid receptor (MOR) and the Dopamine type 2 receptor (D2R), respectively. We utilized a variety of techniques, such as the calcium mobilization assay, a luciferase complementation assay and an electrophysiology assay to study the pharmacology of the CB1R-MOR and CB1R-D2R heteromers. Our data demonstrate that co-expression of CB1R enhances the Gi signaling through MOR and inhibits the beta-arrestin recruitment to MOR. We also show that co-application of CB1R ligands can further accentuate the MOR signaling modulation. Co-expression of a CB1R transmembrane domain 5 (TM5), but not a TM1, mini-gene abrogated the signaling change suggesting that it is likely due to heteromerization of MOR and CB1R. Utilizing this herteromeric signaling could provide a novel therapeutic approach that may yield potent analgesic effects with reduced side effects. We have also found that CB1R switched its signaling specificity from Gi to Gs upon its heteromerizaiton with D2R. In conclusion, our data show that CB1R expands its signaling repertory and modulates the partner receptor signaling upon heteromerization.

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Cavuoto, Paul. "Effect of cannabinoid CB1 receptors on skeletal muscle oxidative pathways /." Title page and abstract only, 2005. http://web4.library.adelaide.edu.au/theses/09SB/09sbc383.pdf.

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Green, Brannon M. "CB1 receptor antagonist AM-251 effect on spatial memory in male mice /." [Chico, Calif. : California State University, Chico], 2009. http://hdl.handle.net/10211.4/83.

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Metna-Laurent, Mathilde. "Cell Type-Specific Control of Memory Functions by CB1 Cannabinoid Receptors." Thesis, Bordeaux 2, 2012. http://www.theses.fr/2012BOR21928/document.

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Le système endocannabinoïde est un important modulateur des fonctions physiologiques. Dans le cerveau, son contrôle s’exerce essentiellement par les récepteurs cannabinoïdes de type 1 (CB1). Les récepteurs CB1 sont abondamment exprimés sur les neurones excitateurs glutamatergiques et les interneurones inhibiteurs GABAergiques et leur stimulation inhibe la libération du glutamate et du GABA. Récemment, l’activité des récepteurs CB1 sur les astrocytes a été proposée comme facilitant la transmission excitatrice. Par ce contrôle général de la neurotransmission, l’activité des récepteurs CB1 induit différents phénomènes de plasticté synaptique associés aux processus de mémoire. Les récepteurs CB1 jouent un rôle complexe dans les fonctions de mémoire. En particulier, la stimulation exogène des récepteurs CB1 perturbe la mémoire de travail. D’autre part, la signalisation endogène des récepteurs CB1 est nécessaire à l’adaptation des réponses de peur apprises. Cependant, les mécanismes par lesquels les récepteurs CB1 régulent ces processus de mémoire n’ont été que peu analysés. L’objectif de ce travail fut de caractériser les mécanismes cellulaires par lesquels les récepteurs CB1 contrôlent la mémoire de travail et les réponses de peur apprises. Nous avons utilisé les modèles de mutation constitutive et conditionnelle des récepteurs CB1 chez la souris afin d’analyser les conséquences de la délétion de ces récepteurs sur des types cellulaires particuliers. Dans une première étude, nous avons montré que les cannabinoïdes exogènes tels que le Δ9-tetrahydocannabinol (THC, principal composé psychoactif du cannabis) induisent des déficits de mémoire de travail spatiale par la stimulation des récepteurs CB1 exprimés sur les astrocytes. Les cannabinoides induisent une forme de dépression à long-terme dans l’hippocampe dont plusieurs mécanismes cellulaires sont similaires à ceux supportant les déficits de mémoire mis en évidence par l’analyse comportementale. Ces résultats suggèrent que les cannabinoïdes altèrent la mémoire de travail spatiale par une modification de la plasticité synaptique de l’hippocampe induite par la stimulation des récepteurs CB1 astrogliaux. Dans une seconde étude, nous avons mis en évidence que les récepteurs CB1 localisés sur les neurones GABAergiques et glutamatergiques exercent un contrôle opposé sur le type de réponse élicité par un stimulus conditioné aversif. La ré-expression sélective des récepteurs CB1 dans l’amygdale des souris mutantes constitutives a permis de préciser l’implication de cette structure dans la régulation des réponses de peur conditionnées par les récepteurs CB1.L’ensemble de ces travaux indiquent que le système endocannabinoïde contrôle les fonctions de mémoire par une régulation de l’activité de cellules spécifiques dans le cerveau. L’implication des astrocytes dans les effets des cannabinoïdes sur la mémoire souligne l’importance de ces cellules dans les processus cognitifs et suggère que les récepteurs CB1 astrogliaux jouent un rôle dans d’autres fonctions cérébrales. Nos résulats révèlent également l’importance de l’évaluation de différents comportements dans le cadre des modèles expérimentaux d’adaptation à la peur The endocannabinoid system is an important regulator of physiological functions. In the brain, this control is mainly exerted through the type-1-cannabinoid (CB1) receptors. CB1 receptors are abundant at excitatory glutamatergic and inhibitory GABAergic neuron terminals where their stimulation inhibits neurotransmitter release. The activity of CB1 receptors on astrocytes has been recently proposed as facilitating excitatory transmission. Through this general control on brain neurotransmission, CB1 receptors mediate distinct forms of synaptic plasticity that are associated with memory processing. Indeed, CB1 receptors control memory functions. In particular, the exogenous stimulation of CB1 receptors impairs working memory. Moreover, the endogenous CB1 receptor signalling ensures the adaptation of learned fear responses. However, the brain mechanisms of this CB1-mediated control of memory functions are poorly characterized. The goals of this research work were to dissect the cellular mechanisms by which CB1 receptors control both working memory and learned fear responses. We used constitutive and conditional mutagenesis in mice to address the roles of CB1 receptors on particular cell types in these functions. We first showed that exogenous cannabinoids, including Δ9-tetrahydocannabinol (THC, the main psychoactive constituent of cannabis), impairs spatial working memory through the stimulation of astroglial CB1 receptors. Cannabinoids also induce a form of in vivo long-term depression in the hippocampus that shares several cellular mechanisms with the cannabinoid-induced working memory impairments. These results suggest that cannabinoids disrupt spatial working memory by altering hippocampal synaptic plasticity through astroglial CB1 receptor stimulation. We then showed that CB1 receptors expressed on GABAergic and glutamatergic neurons oppositely control fear coping strategies in the presence of fear conditioned stimuli. The selective and local re-expression of CB1 receptors in the amygdala of constitutive CB1 mutant mice allowed to precise the involvement of this brain structure in the regulation of conditioned fear responses by CB1 receptors. Altogether, these studies indicate that the endocannabinoid system differentially controls memory functions through its distinct modulation of the activity of specific brain cells. The involvement of astrocytes in the effects of cannabinoids on memory highlights their key roles in cognitive processes and further suggests that astroglial CB1 receptors might play a role in other high order brain functions. Our results also point the importance of performing thorough behavioral analyses in the experimental models of fear adaptation

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34

Collier, Lauren Michele. "Relationship Between CB1 and S1P Receptors in the Central Nervous System." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/733.

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There is significant sequence homology and anatomical co-distribution between cannabinoid (CB1) and sphingosine-1-phosphate (S1P) receptors in the CNS, but potential functional relationships between these lysolipid receptors have not been examined. Therefore, to investigate possible relationships between these two systems at the level of G-protein activation, agonist-stimulated [35S]GTPγS binding and autoradiography were conducted. Autoradiographic studies were first performed to localize receptor-mediated G-protein activation in mouse brain. Coronal brain slices were processed for stimulation of [35S]GTPγS binding using the synthetic cannabinoid agonist WIN 55,212-2 (WIN) or SIP. High levels of WIN- and S1P-stimulated [35S]GTPγS binding were observed in the caudate putamen, hippocampus, substantia nigra, and cerebellum. To further characterize the relationship between S1P-and CB1-mediated G-protein activation, spinal cords from adult male CB1 receptor knockout mice, CNS-deleted S1Pl receptor knockout mice and wild type C57 mice were collected, and assessed using agonist-stimulated [35S]GTPγS binding. Results from this experiment revealed that the S1Pl receptor is predominant in mouse spinal cord. To further investigate potential CBl and SIP receptor interactions spinal cords were collected from adult male ICR mice. Additivity studies were preformed using agonist-stimulated [35S]GTPγs binding. Results showed significantly less than additive stimulation when spinal cord tissue was treated with both WIN and SIP. These results suggest an interaction between the CB1 and S1P receptors in the mouse spinal cord. The effect of cannabinoid antagonists, SR141716A (CB1) and SR144528 (CB2) on S1P-and WIN-stimulated [35S]GTPγS binding were also examined in mouse spinal cord homogenates. These results showed that there was no significant difference between S1P-stimulated [35S]GTPγS binding in the presence of SR141716A or SR144528 compared to vehicle control. This shows that S1P produced stimulation independent of the CBl or CB2receptor. In addition WIN-stimulated [35S]GTPγS binding was not affected by SR144528, but was inhibited by SR141716A, confirming that this action is due to the CB1 receptor. The combined results of this project demonstrate an interaction between CB1 and S1P receptors in certain CNS regions where they are co-distributed, such as the caudate putamen, hippocampus, substantia nigra, cerebellum and spinal cord. These results may be due to convergence on a common pool of G-proteins via dimerization or co-localization in lipid rafts, or a possible direct ligand-receptor interaction.

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35

Bernardes, Terzian Ana Luisa. "Behavioral phenotypes of mice lacking cannabinoid CB1 receptors in different neuronal subpopulations." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-170356.

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Abnormalities in social behavior are found in almost all psychiatric disorders, such as anxiety, depression, autism and schizophrenia. Thus, comprehension of the neurobiological basis of social interaction is important to better understand numerous pathologies and improve treatments. Several evidences suggest that an alteration of cannabinoid CB1 receptor function could be involved in the pathophysiology of such disorders. However, the role of CB1 receptor is still unclear and its localization on different neuronal subpopulations may produce distinct outcomes. To dissect the role of CB1 receptor on different neuronal population, male mice were used – knockout mice and their respective control littermates [total deletion (CB1-/-); specific deletion on cortical glutamatergic neurons (GluCB1-/-); on GABAergic neurons of the forebrain (GABACB1-/-); or on dopaminergic D1 receptor expressing neurons (D1CB1-/-)], and wild-type (WT) mice treated with CB1 antagonist/inverse agonist SR141716A (3mg/kg). To elucidate the behavioral effects of specific CB1 receptor deficiency, D1CB1-/- mice were submitted to a battery of behavioral tests which included exploration-based tests, depressive-like behavioral tests, and fear-related memory paradigms. It was demonstrated that D1CB1-/- mice exhibited significantly increased contextual and auditory-cued fear, with attenuated within-session extinction. Also, when all mice lines were submitted to different social tasks, involving male or female as the stimulus subject, GluCB1-/- mice showed reduced interest for the social stimulus, as CB1-/- or WT treated with SR141716A mice. D1CB1-/- showed moderate changes in social interest, and GABACB1-/- mice showed the opposite phenotype by spending more time investigating the social stimulus. In conclusion, specific reduction of endocannabinoid signaling in D1-expressing neurons is able to affect acute fear adaptation. Moreover, CB1 receptors specifically modulate social investigation of female mice in a cell-specific manner. These findings support the involvement of cannabinoid signaling in social alterations in psychiatry disorders.

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Ibrahim, Mohab Mohamed. "Pain-modulating effects of peripheral (CB2) cannabinoid receptors." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/280554.

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Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence implicates the CB1, receptor in the production of antinociception, inflammatory hyperalgesia, and peripheral nerve injury-induced sensory hypersensitivity. In previous work included in my masters thesis, our laboratory has demonstrated the capacity of CB2 receptors located outside the central nervous system (CNS) to inhibit acute nociception and inflammatory hyperalgesia. In this thesis, I use AM1241, a CB2 receptor-selective agonist to test the hypothesis that CB2 receptor activation reverses the tactile and thermal hypersensitivity characteristic of neuropathic pain in L5/L6 spinal nerve ligation model. The CB2 receptor-mediated nature of these effects was demonstrated using receptor-selective antagonists, as well as mice deficient in the genes coding for CB1 or CB2 receptors. Experiments using site-specific injections suggest AM1241 acts peripherally at the site of nerve injury and the site of application of the sensory stimulus. The peripheral nature of the effects of AM1241 is consistent with the peripheral distribution of CB 2 receptors. Given the peripheral actions of AM1241, I hypothesized and demonstrated that topical application of AM1241 modulates pain responses. Additionally, I began to examine the mechanisms by which CB2 receptor activation modulates pain responses. The effects of AM1241 were reversed by the opioid receptor antagonist, naloxone and by a sequestering antiserum to beta-endorphin. In addition, the effects of AM1241 were not observed in beta-opioid receptor knockout mice. These results suggest that the endogenous opioid peptide, mu-endorphin plays an essential role in CB2 receptor mediated pain inhibition. Further, AM1241 stimulated release of beta-endorphin from rat skin tissue and cultured human keratinocytes. The stimulation of beta-endorphin release by AM1241 was inhibited by the CB2 receptor-selective antagonist, AM630, and was not observed in skin from CB2 receptor knockout mice, demonstrating that it is mediated by CB2 receptor. These results suggest that CB2 receptor activation produces antinociception by stimulating the release of beta-endorphin from local cells and that beta-endorphin released acts at beta-opioid receptors to inhibit the responsiveness of primary afferent neurons.

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37

Elmes, Steven. "Cannabinoid CBâ‚‚ receptor activation inhibits acute and inflammatory pain." Thesis, University of Nottingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420331.

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Netherland, Courtney Denise. "Role of Type 2 Cannabinoid Receptor (CB2) in Atherosclerosis." Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etd/1392.

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Atherosclerosis is a macrophage-dominated nonresolving inflammatory disease of the arterial wall. Macrophage processes, including apoptosis, influence lesion development in atherosclerosis. Cannabinoids, compounds structurally related to Δ9-tetrahydrocannabinol (THC), the active ingredient in marijuana, exert their effects through cannabinoid receptors, CB1 and CB2. Cannabinoid treatment, THC or Win55,212-2, reduces atherosclerosis in ApoE-null mice by a mechanism thought to involve CB2. However, the exact role of CB2 in atherosclerosis remains unclear. We found that CB2-null macrophages are resistant to oxysterol/oxLDL-induced apoptosis leading us to hypothesize that CB2 may modulate macrophage apoptosis in atherosclerosis. To determine the functions of CB2 in atherosclerosis, we fed low density lipoprotein receptor-null (Ldlr-/-) and Ldlr-/- mice genetically deficient in CB2, an atherogenic diet for 8 and 12 weeks. CB2 deficiency did not significantly affect aortic root lesion area after 8 or 12 weeks; however, after 12 weeks, CB2-deficient lesions displayed increased lesional macrophage and smooth muscle cell (SMC) content and a ~2-fold reduction in lesional apoptosis. CB2-deficienct lesions also displayed reduced collagen content and elevated elastin fiber fragmentation that was associated with elevated levels of the extracellular matrix degrading enzyme, matrix metalloproteinase 9 (MMP9). These results demonstrate that although CB2 signaling does not affect atherosclerotic lesion size it does modulate lesional apoptosis, cellularity and ECM composition. Ldlr-/- and CB2-deficient Ldlr-/- mice were also subjected to daily treatments with Win55,212-2, a synthetic cannabinoid, over the last 2 weeks of an 8 week atherogenic diet to identify CB2-dependent and CB2-independent effects of cannabinoid receptor stimulation on atherosclerosis. Win55,212-2 did not affect hypercholesterolemia, aortic root lesion area, lesional macrophage infiltration, or ECM composition in either genotype but did significantly reduce total plasma triglyceride levels and lesional SMC content, independent of CB2. Surprisingly, lesional apoptosis was dose-dependently repressed by Win55,212-2 in Ldlr-/- mice by a CB2-dependent mechanism. All together, these results support the suggestion that CB2 may be a target for novel therapies aimed at modulating lesional apoptosis and cellularity to increase lesion stability and reduce the vulnerability to rupture.

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39

Robin, Laurie. "Roles of astroglial cannabinoid type 1 receptors (CB1) in memory and synaptic plasticity." Thesis, Bordeaux, 2018. http://www.theses.fr/2018BORD0283/document.

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Le système endocannabinoïde est un important modulateur des fonctions physiologiques. Il est composé des récepteurs aux cannabinoïdes, de ses ligands lipides endogènes (les endocannabinoïdes) et de la machinerie enzymatique pour leur synthèse et leur dégradation. Les récepteurs aux cannabinoïdes de type 1 (CB1) sont exprimés dans différents types cellulaires dans le cerveau et sont connus pour être impliqués dans les processus mnésiques. Les endocannabinoïdes sont mobilisés dépendamment de l’activité notamment dans les régions cérébrales impliquées dans la mémoire telle que l’hippocampe. Dans cette région, les récepteurs CB1 sont exprimés au niveau des terminaisons neuronales présynaptiques où leur stimulation inhibe la libération de neurotransmetteurs, modulant ainsi différentes formes d’activité synaptique. Outre leur expression sur les neurones, les récepteurs CB1 sont également exprimés par les astrocytes. Avec l’élément pré- et post-synaptique, les astrocytes font partis de la « synapse tripartite » où ils participent à la plasticité synaptique et les processus mnésiques associés. De manière intéressante, la stimulation des récepteurs CB1 astrocytaires facilite la transmission glutamatergique dans l’hippocampe. Dans cette région, les astrocytes régulent l’activité des N-methyl-Daspartate receptors (NMDARs) à travers le contrôle des niveaux synaptiques de leur co-agoniste, la D-serine, modulant ainsi la plasticité synaptique à long terme. Cependant, le mécanisme entrainant la libération de D-serine par les astrocytes n’est pas identifié. De manière intéressante, notre laboratoire a montré que les effets délétères des cannabinoïdes exogènes sur la mémoire de travail spatial sont médiés par les récepteurs CB1 astrocytaires à travers un mécanisme dépendant des NMDARs dans l’hippocampe. Cependant, le rôle physiologique des récepteurs CB1 astrocytaires restent méconnus. Une des formes de mémoire impliquant le récepteurs CB1 est la mémoire de reconnaissance d’objet (NOR). La stimulation exogène des récepteurs CB1 hippocampique inhibe la consolidation de la NOR mais la délétion constitutive des récepteurs CB1 n’affecte pas la NOR, suggérant que la signalisation des récepteurs CB1 endogènes n’est pas nécessaire. Cependant, de récentes études soulignent que la délétion globale du gène CB1 pourrait masquer le rôle des récepteurs CB1 des différents types cellulaires. Ceci indique la nécessité de nouveaux outils plus sophistiqués afin de totalement comprendre le rôle physiologique du système endocannabinoïde dans des comportements complexes. Dans cette étude, nous avons étudié le rôle physiologique des récepteurs CB1 astrocytaires dans la formation de la NOR et la plasticité synaptique. En utilisant une combinaison d’approches génétiques, comportementales, électro-physiologiques, d’imagerie et de biochimie, nous avons montré que l’activation endogène des récepteurs CB1 astrocytaires est nécessaire pour la consolidation de la NOR à long terme, et ceci à travers un mécanisme impliquant l’apport en D-sérine, afin de stimuler l’activité des NMDARs synaptiques de l’hippocampe dorsal. Cette étude révèle un mécanisme inattendu à la base de la libération de D-sérine, entrainant l’activité des NMDARs et la formation de la mémoire à long terme The endocannabinoid system is an important modulator of physiological functions. It is composed of cannabinoid receptors, their endogenous lipid ligands (the endocannabinoids) and the enzymatic machinery for endocannabinoid synthesis and degradation. The type-1 cannabinoid receptors (CB1) are expressed in different cell types of the brain and are known to be involved in memory processes. Endocannabinoids are mobilized in an activity-dependent manner in brain areas involved in the modulation of memory such as the hippocampus. In this brain region, CB1 receptors are mainly expressed at neuronal pre-synaptic terminals where their stimulation inhibits the release of neurotransmitters, thereby modulating several forms of synaptic activity. Besides their expression in neurons, CB1 receptors are also expressed in astrocytes. Along with the pre- and post-synaptic neurons, astrocytes are part of the “tripartite synapse”, where they participate in synaptic plasticity and associated memory processes. Interestingly, modulation of astroglial CB1 receptors has been proposed to facilitate glutamatergic transmission in the hippocampus. In this brain area, astrocytes regulate the activity of N-methyl-D-aspartate receptors (NMDARs) through the control of the synaptic levels of their co-agonist D-serine, thereby mediating long-term synaptic plasticity. However, the mechanisms inducing D-serine release by astrocytes are still not identified. Interestingly, our laboratory showed that the negative effect of exogenous cannabinoids on spatial working memory is mediated by astroglial CB1 receptors through a NMDAR-dependent mechanism in the hippocampus, but the physiological role of astroglial CB1 remains unknown. One of the forms of memory involving CB1 receptors is novel object recognition (NOR) memory. The exogenous stimulation of hippocampal CB1 receptors inhibits the consolidation of long-term NOR formation. Constitutive global deletion of CB1 receptors in mice leaves NOR memory intact, suggesting that endogenous CB1 receptor signaling is not necessary for long-term NOR. However, recent studies pointed-out that, likely due to compensatory mechanisms, the global deletion of the CB1 gene might mask cell type-specific roles of CB1 receptors, indicating that more sophisticated tools are required to fully understand the physiological roles of the endocannabinoid system in complex behavioral functions. In this work, we investigated the physiological role of the astroglial CB1 receptors on NOR memory formation and synaptic plasticity. By using a combination of genetic, behavioral, electrophysiological, imaging and biochemical techniques, we showed that endogenous activation of astroglial CB1 receptors is necessary for the consolidation of long-term NOR memory, through a mechanism involving the supply of D-serine to enhance synaptic NMDARs-dependent plasticity in the dorsal hippocampus. This study uncovers an unforeseen mechanism underlying D-serine release, triggering NMDARs activity and long-term memory formation.ory

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Holt, Christopher James. "Design, synthesis and evaluation of fluorescent CB2 cannabinoid receptor ligands." Thesis, University of Nottingham, 2009. http://eprints.nottingham.ac.uk/10712/.

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Cannabis has been used as a medicinal and natural product for thousands of years. Whether it has been used to make rope or paper, or been used to treat pain or depression, cannabis has always had a place in human civilisation. With the isolation of the psychoactive compounds responsible for cannabis’ effects, the discovery of two human cannabinoid receptors and an expanding knowledge of the therapeutic uses of cannabis, interest in the development of novel cannabinoids grew. The CB2 cannabinoid receptor has gained particular attention, as the often unwanted central and psychoactive effects of cannabinoids has been attributed to the CB1 cannabinoid receptor. Development of CB2 receptor selective ligands offers treatment opportunities in many areas, but most especially for pain, multiple sclerosis and immunomodulation. The preparation of fluorescently labelled ligands for a variety of receptors has improved compound screening techniques, as well as allowing use as biomolecular probes for aiding our understanding of the receptor in situ. The aim of this work is to design, synthesise and evaluate novel fluorescently labelled cannabinoids, with a particular interest in CB2 selective compounds. Focusing on the CB2 receptor selective alkylindole JWH-015, targeted substitutions were made to its naphthyl ring to identify sites that might be suitable for fluorophore attachment. With a site chosen, a series of fluorescent JWH-015 analogues was synthesised and evaluated for their CB2 receptor binding affinities. Though none of the evaluated compounds showed sufficient binding affinity for them to be used as biomolecular tools, the structure activity relationships gained suggested that improved design of fluorescent JWH-015 analogues in future could lead to the first ever active fluorescent cannabinoid.

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41

Òdena, Garcia Gemma. "Paper del receptor de cannabinoides 1 (CB1) a la Cirrosi experimental. Efecte del bloqueig de CB1 sobre les complicacions de la cirrosi." Doctoral thesis, Universitat Autònoma de Barcelona, 2011. http://hdl.handle.net/10803/83997.

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La cirrosi és una malaltia crònica, difusa i considerada irreversible, caracteritzada per l’alteració de l’arquitectura vascular hepàtica provocada pel reemplaçament del teixit parenquimàtic per teixit fibròtic, així com per l’aparició de nòduls de regeneració. Aquesta destrucció del teixit hepàtic i la seva substitució per teixit fibrós provoca un augment marcat de la resistència al flux de la vena porta, així com una greu alteració de la funció hepàtica. A més d’un risc augmentat d’aparició de càncer hepàtic, les complicacions més freqüents i potencialment mortals de la cirrosi, associades a la hipertensió portal, són l’hemorràgia digestiva, l’ascites i trastorns de la funció renal, les infeccions bacterianes i l’encefalopatia hepàtica. S’han utilitzat diverses estratègies terapèutiques per evitar o disminuir la gravetat de les complicacions de la cirrosi, tot i que en la majoria de casos la seva eficàcia és escassa o presenten contraindicacions. És important doncs desenvolupar altres estratègies dirigides a evitar o revertir el dany hepàtic. Considerem, en aquesta línia, que el sistema endocannabinoide de senyalització podria ser una bona diana terapèutica. Aquest sistema està format per cannabinoides endògens, així com pels seus receptors específics (CB1, CB2 i altres) i els seus enzims de síntesi i degradació. El desenvolupament de molècules agonistes i antagonistes selectives d’aquests mediadors ha permès conèixer la seva acció biològica i assajar possibles tractaments de diverses malalties, entre elles les complicacions associades a la cirrosi. Concretament el bloqueig del receptor CB1 mitjançant l’antagonista rimonabant ha mostrat, en diversos estudis, efectes beneficiosos en la progressió de la fibrosi, alteracions hemodinàmiques i formació d’ascites, sobretot en administració aguda o pretractament a llarg termini. A més, en estudis experimentals d’encefalopatia hepàtica per dany hepàtic fulminant, s’han observat millores a les funcions neurològiques, dosi-depenents de l’administració d’antagonistes del receptor CB1. Tot i que l’expressió de CB1 de cèl·lules de Kupffer i estelades està augmentada en fetges cirròtics, podria ser que els hepatòcits també estiguessin implicats de manera rellevant a través de l’activació dels seus receptors CB1 a la progressió de la fibrosi. Així doncs, l’objectiu principal d’aquesta tesi fou investigar l’efecte del tractament a llarg termini amb rimonabant en un model de cirrosi avançada, sobre la fibrosi i la cirrosi, avaluar el seu efecte sobre l’incidència de translocació bacteriana, l’hemodinàmica sistèmica i en el desenvolupament d’encefalopatia hepàtica en rates cirròtiques ascítiques, així com establir el paper del receptor CB1 dels hepatòcits sobre la progressió de la fibrosi. Per aquest motiu es va dissenyar un primer estudi experimental in vivo en el que es va administrar rimonabant a llarg termini a rates cirròtiques amb ascites per tal de valorar l’efecte sobre la progressió de la cirrosi, i sobre les complicacions associades, com les alteracions hemodinàmiques, la translocació bacteriana i l’encefalopatia hepàtica. Un segon estudi in vitro amb cultius primaris de hepatòcits de rates cirròtiques ens va permetre avaluar el paper dels hepatòcits i la seva relació amb el sistema endocannabinoide de senyalització en la progressió de la cirrosi. D’acord amb els resultats obtinguts d’aquests dos estudis vam poder concloure que el tractament a llarg termini amb rimonabant disminueix la fibrosi i millora l’hemodinàmica esplàcnica i sistèmica així com alguns paràmetres de funció hepàtica. Això s’associa amb una reducció de la translocació bacteriana. A més, redueix l’amoni cerebral i l’edema cerebral de baix grau. Rimonabant podria ser útil per algunes de les complicacions associades a la cirrosi com les infeccions bacterianes i l’encefalopatia hepàtica. Pel que fa al paper dels hepatòcits a la cirrosi experimental per tetraclorur de carboni, sembla que aquest seria limitat. Cirrhosis is a chronic disease characterized for the alteration of hepatic vascular architecture due to the replacement of parenchymal tissue with fibrotic tissue. This hepatic tissue destruction and its substitution with fibrotic tissue leads to the increased resistance to portal vein flow and to serious alteration of hepatic function. Aside from development of hepatic cancer, the most common complications of cirrhosis, associated to portal hypertension, are gastrointestinal bleeding, ascites and renal malfunction, bacterial infections and hepatic encephalopathy. Several therapeutic strategies had been used to avoid or decrease severity of cirrhosis complications, although its effectiveness is low or they present contraindications. Therefore, there is a need of new strategies than avoid or revert hepatic damage. Considering this, the endocannabinoid system of signaling could represent a new therapeutic target. This system is composed by endogen cannabionids, their specific receptors (CB1, CB2 and others) as well as by the respective synthesis and degradation enzymes. The development of selectives agonists and antagonists for these molecules enabled to learn about their biological activity as well as to test their use as a treatment on different diseases, among them cirrhosis. Specifically the blockade of CB1 receptor by its antagonist rimonabant has show to be beneficial in the progression of fibrosis, hemodynamic alterations and ascites formation, mainly in acute administration or long term pretreatment experimental studies. Further, in hepatic encephalopathy experimental studies by means of fulminant liver damage, improvement on neurological functions when administering CB1 receptor antagonists has been reported. Even if CB1 expression on Kupffer cells and stellate cells is increased in cirrhotic livers, hepatocytes may as well be involved in fibrosis progression through CB1 receptor activation. So, the aim of the present thesis was assess the effect of Rimonabant long-term administration on fibrosis and cirrhosis, bacterial translocation, hemodynamic alterations and hepatic encephalopathy development in ascitic cirrhotic rats, as well as to establish the role of hepatocyte receptor CB1 on progression of fibrosis. To do so, firstly an in vivo experimental study was designed. In this study we administered rimonabant for a ten days to cirrhotic ascitic rats in order to assess its effect on cirrhosis progression and its associated complications. Secondly, an in vitro study with primary cultured hepatocytes from cirrhotic rats allowed as to assess the role of hepatocytes and their relations with the endocannabinoid system regarding progression of cirrhosis. According to our results, long-term rimonabant administration improves fibrosis, splachnic and systemic vasodilatation and some liver function parameters. This is associated with a reduction in bacterial translocation incidence. Moreover, long-term treatment reduces brain ammonia leading to a decrease of low grade brain edema. Rimonabant could be a useful therapy for some complications associated with cirrhosis such as bacterial infections and hepatic encephalopathy. In terms of the role of hepatocytes on experimental cirrhosis by carbon tetrachloride, it seems it is not relevant.

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42

Dodd, Garron. "Appetite and functional brain responses to cannabinoids." Thesis, University of Manchester, 2010. https://www.research.manchester.ac.uk/portal/en/theses/appetite-and-functional-brain-responses-to-cannabinoids(b2b4f7e8-d711-421e-867e-fcf017bfccf0).html.

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The obesity epidemic is a major health threat affecting one in four people in the affluent western world, where high-energy foods are easily available and there is little need for exercise. To identify novel therapeutic targets for the treatment of obesity, one important step is to further define the complex circuitry in the brainwhich is ultimately responsible for our appetite and body weight regulation. Although complex, appetite can be thought of as having two distinct, though none mutually exclusive, aspects: the need to eat (homeostatic) and the desire to eat(hedonistic).The need to eat, a product of energy homeostasis, is what drives the consumption offood for basic survival. In an attempt to further define the mainly “homeostatic” neuronal circuitry, we combined blood-oxygen-level-dependent (BOLD)pharmacological-challenge magnetic resonance imaging (phMRI) with c-Fosfunctional activity mapping to characterise “whole brain” responsiveness to anorexigenic dose of the glucose anti metabolite 2-deoxy-D-glucose (2-DG). Using thesecomplementary methods, we demonstrated functional brain activity in a number ofknown glucose-sensing brain regions, including parts of the hypothalamus andbrainstem, following administration of 2-DG when compared with vehicle treatment.The desire to eat is a result of a complex interplay between the reward andmotivational circuits implicated in addictive behaviours, and those which controlenergy homeostasis. Recent research has pointed to the endocannabinoid system,and specifically the central cannabinoid 1 (CB1) receptor, as a key target mediatingthe functional cross talk between the two appetitive systems. To define the sites ofaction of cannabinoids, we used an orexigenic dose of the full CB1 agonist, CP55940,to map responsive brain regions again using BOLD phMRI and whole-brain c-Fosfunctional activity mapping. Areas of interest demonstrated a drug interaction whenthe CB1 receptor inverse agonist, Rimonabant was co-administered. These complementary methods demonstrated functional activity in the cortico-striatalhypothalamicpathway, a key system in the motivational drive to eat.The appetitive actions of synthetic CB1 inverse agonists such as Rimonabant are welldocumented. We, however, described a putative novel endogenous CB1 inverseagonist, hemopressin, which is the first identified peptide ligand of CB1 receptors.We showed that hemopressin inhibits agonist-induced receptor internalisation in aheterologous cell model in vitro. When administered centrally or systemically in vivo,we found that hemopressin decreases nocturnal food intake in out-bred rats andmice, as well as in obese, leptin-deficient ob/obmice. Importantly, hemopressininduces hypophagia without causing any apparent adverse side effects. We have also shown that the anorectic effect is absent in CB1-/- mice, and that hemopressin canblock CB1 agonist-induced hyperphagia in male rats, providing strong evidence forantagonism of the CB1 receptor in vivo. We speculate that hemopressin may be one of a family of endogenous functional CB1 receptor ligands that modulate the activity of appetite pathways in the brain.

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43

Ramírez, López Ángela 1992. "Role of CB2 cannabinoid receptor in nociception and food intake control." Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2021. http://hdl.handle.net/10803/672620.

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The endocannabinoid system is a natural modulatory system that participates in multiple physiological processes, including nociceptive, emotional and rewarding responses. These central responses are mainly mediated by cannabinoid receptor 1 (CB1R)-dependent mechanisms, although the side effects associated to these central responses limit the therapeutic use of CB1R agonists. Recent research on the cannabinoid receptor 2 (CB2R) provides an alternative approach to avoid the central side effects associated with CB1R stimulation. The purpose of this Thesis was to investigate the involvement of CB2R in two different pathological conditions that currently lack effective treatment: neuropathic pain and food addiction. The results revealed that the pain-resistant phenotype of Fmr1KO mice against the nociceptive and emotional manifestations triggered by persistent nerve damage requires the participation of CB2R. We also demonstrated that CB2R are involved in the neurobiological substrate underlying the behavioral and affective alterations that arise from food addiction. Altogether, these data highlight the potential therapeutic interest of targeting CB2R for the treatment of neuropathic pain, food addiction disorders and their co-morbid emotional manifestations. El sistema endocannabinoide es un sistema modulador natural que participa en múltiples procesos fisiológicos, incluidas las respuestas nociceptivas, emocionales y de refuerzo. Estas respuestas centrales están mediadas principalmente por mecanismos dependientes del receptor cannabinoide 1 (CB1R), aunque los efectos secundarios asociados a estas respuestas centrales limitan el uso terapéutico de agonistas de CB1R. La investigación reciente sobre el receptor cannabinoide 2 (CB2R) proporciona un enfoque alternativo para evitar los efectos secundarios centrales asociados con la estimulación de CB1R. El propósito de esta Tesis era investigar la implicación de CB2R en dos condiciones patológicas diferentes que actualmente carecen de tratamiento efectivo: el dolor neuropático y la adicción a la comida. Los resultados revelaron que el fenotipo resistente al dolor de los ratones Fmr1KO frente a las manifestaciones nociceptivas y emocionales desencadenadas por un daño nervioso persistente requiere la participación del CB2R. También demostramos que los CB2R están involucrados en el sustrato neurobiológico subyacente a las alteraciones conductuales y afectivas que surgen de la adicción a la comida. En conjunto, estos datos destacan el potencial interés de utilizar CB2R como diana terapéutica para el tratamiento del dolor neuropático, los trastornos de adicción a la comida y sus manifestaciones emocionales comórbidas.

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44

Raborn, Erinn Shenee. "Cannabinoid Modulation of Chemotaxis of Macrophages and Macrophage-like Cells." VCU Scholars Compass, 2007. http://hdl.handle.net/10156/1333.

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45

Fulmer, Makenzie. "Role of Cannabinoid Receptor Type 2 (CB2) in Late Stage Atherosclerosis." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etd/3328.

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Atherosclerosis is a chronic inflammatory disorder of medium and large vessels. Immune signaling and dyslipidemia are two of several processes which influence lesion development in atherosclerosis. Cannabinoids, such as those found in marijuana, exert their effects through two cannabinoid receptors, CB1 and CB2. Recent studies using CB2 knockout mice and CB2-selective ligands have shed light on a protective role of CB2 in early stages of atherosclerosis. However, the role of CB2 in advanced stages of atherosclerosis remains unclear. To determine if CB2 plays a role in advanced atherosclerotic lesion composition and progression, we investigated the effects of systemic CB2 gene deletion on advanced atherogenesis in Ldlr-null mice fed an atherogenic high fat diet (HFD) for 20-24 weeks. CB2 deficiency did not significantly affect aortic root lesion area, however, CB2-/- mice had a significant increase (~1.9 fold) in the percentage of abdominal aorta surface occupied by lesion. CB2-/- mice also displayed increased lesional macrophage content (~2.3 fold) and an unstable phenotype characterized by significantly reduced smooth muscle cell/macrophage ratio and increased matrix metalloproteinase-9 activity and mineralization. These results suggest that although CB2 does not affect the size of atherosclerotic lesions, it does modulate the cellular and extracellular matrix composition and promotes a stable phenotype. CB2+/+ and CB2-/- mice were also subjected to treatments with either CB2-selective agonist, JWH-015, or antagonist, SR144528, over the last four weeks of a 24 week atherogenic diet to identify the effects of CB2 stimulation on calcification of advanced lesions. No change was observed in body weight or cholesterol in response to either treatment. SR144528 reduced triglycerides and mineralization of aortic root lesions in CB2+/+ mice only. Aortic Runx2 and osteopontin were increased in response to JWH-015 by a CB2-dependent mechanism. Administration of synthetic cannabinoids in an ex vivo organ culture of CB2+/+ aortas revealed increased vascular calcification in response to CB2 blockade and decreased vascular calcification in response to CB2 activation. All together, these results support a protective role for CB2 in late stages of atherosclerosis and suggests that drugs targeting CB2 may be beneficial in the treatment of advanced atherosclerosis by affecting osteogenic mechanisms implicated in the mineralization of lesions.

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46

Hepburn, Claire Y. "Studies investigating the mechanisms of the cardioprotective effects of cannabidiol." Thesis, Robert Gordon University, 2014. http://hdl.handle.net/10059/1002.

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The phytocannabinoid cannabidiol (CBD) has a complex pharmacology which is thought to include, but is not limited to, an ability to act as an inverse agonist at the CB1 and CB2 receptors and an antagonist of GPR55. Moreover, is has been shown to reduce infarct size and ameliorate reductions in left ventricular function in vivo. These improvements in the pathogenesis of experimental MI are accompanied by a reduction in inflammatory cell migration to the area at risk. More recently it has been shown that CBD is anti-arrhythmic in acute experimental MI. Thus, it was suggested that the cardioprotective effects of CBD might be due to an anti-inflammatory action. In addition, GPR55 receptor activation is acknowledged to mediate mobilisation of intracellular Ca2+ (Ca2+i) which could potentially be pro-arrhythmic and so CBD, as an antagonist may confer cardioprotection via GPR55. However, the receptors and/or mechanisms responsible for mediating the cardioprotective effects of CBD are get to be determined. The present studies were therefore performed to; (1) better understand the pharmacology of CBD by assessing haemodynamic responses to CBD and other cannabinoids ligands in anaesthetised rats, (2) investigate the receptors involved in the anti-arrhythmic effect of CBD in a rat model of coronary artery occlusion (CAO), and (3) investigate if CBD can alter [Ca2+]i in isolated rat cardiomyocytes. The characterisation of the pharmacology of CBD in vivo showed that; firstly, CB1 receptor activation causes a hypotensive response which can be dose-dependently inhibited by AM251; secondly, both CBD and AM251 alone (a CB1 receptor antagonist and GPR55 agonist) can induce vasodepressor responses and finally, CBD can potentiate the AM251-mediated hypotension when co-administered, suggesting possible cross-talk between the CB1 and GPR55. Results from CAO studies showed that CBD and AM251 each have the capacity to reduce arrhythmias. Moreover, when CBD and AM251 were co-administered the anti-arrhythmic capacity of either alone was potentiated. However, the degree of potentiation was dependent on the order of administration, suggesting that more than one receptor is involved in the summative anti-arrhythmic effects. The investigation of cardiomyocyte [Ca2+]i suggested that AM251 can modulate [Ca2+]i at the level of the cardiomyocyte, while CBD cannot. These data give novel insight into the anti-arrhythmic effects of CBD and, moreover, for the first time demonstrate that AM251 is anti-arrhythmic. In addition, these data suggest a role for GPR55 in increasing [Ca2+]i via AM251.

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47

Falenski, Katherine Winslow. "Functional Redistribution of Hippocampal Cannabinoid Cb1 Receptors in the Rat Pilocarpine Model of Acquired Epilepsy." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/1280.

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Cannabinoids, such as the marijuana derivative Δ9-THC, are known to have CBl receptor-mediated anticonvulsant effects in several animal models of seizures and epilepsy, including the rat pilocarpine model of acquired epilepsy. However, the distribution of CBl receptor expression and function in brains of epileptic rats has not been characterized. Therefore, this dissertation was initiated to evaluate the effect of epileptogenesis on the distribution and function of the endogenous CBI receptor system in the rat pilocarpine model, a well-established model of acquired temporal lobe epilepsy. Using immunohistochemistry, we demonstrated that chronically epileptic rats exhibit a unique, long-term, and specific redistribution of hippocampal CBl receptors when compared to controls, with concurrent layer-specific increases and decreases in CBl receptor expression within the hippocampus. In addition, studies in this dissertation demonstrated using [3H] WIN55,212-2 autoradiography and agonist-stimulated [35S]GTPγS autoradiography that this CBl receptor-specific reorganization results in corresponding functional changes manifested by alterations in CBl receptor binding and G-protein activation. These regionally selective changes were dependent on NMDA receptor activation during the initial insult of pilocarpine-induced status epilepticus (SE), and were independent of seizure suppression produced with phenobarbital administration in epileptic rats. Furthermore, time-course studies utilizing these techniques demonstrate that within a week following SE, a widespread loss of CBl receptor expression and function occurs throughout the hippocampus. The subsequent redistribution of CBl receptors that occurs temporally correlates with the emergence of spontaneous recurrent seizures, and is still observed up to 1 year following SE. Overall, the reorganization of cannabinoid receptors in epilepsy implicates the endocannabinoid system in modulating neuroexcitability in the epileptic state. This CBl receptor redistribution represents an essentially permanent neuronal plasticity change associated with epileptogenesis, and could account for the anticonvulsant effect of cannabinoids observed in this model.

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48

Kossatz, de Mello Elk 1977. "Neuroprotective mechanisms of CB2 cannabinoid receptors and PPAR-α in hypoxia/ischemia-induced brain damage". Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/664430.

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In this thesis, we have developed a hypoxia-ischemia (HI) model in adult mice to study the neuroprotective mechanisms of CB2 cannabinoid receptors (CB2R), and the potential therapeutic effects of the new PPAR-α agonist, octadecylpropyl sulfamide (SUL). First, we determined the behavioural and cognitive alterations induced by HI in CB2R knockout (KO) mice and wild-type (WT) littermates, as well as, the cellular and molecular alterations associated with brain injury. Second, we evaluated the effects of SUL on the behavioural and cognitive alterations induced by HI in C57BL/6J adult mice, and studied the associated neurodegeneration processes, and changes in gene expression related to the neuroinflammation/endocannabinoid signalling systems in the brain. Our findings suggest that CB2R confer neuroprotection following HI insult through the modulation of the microglial pro-inflammatory factors HIF-1α and TIM-3 acting as a defensive mechanism to reduce subsequent behavioural alterations. In addition, we demonstrated that the potent and stable PPAR-α agonist, SUL administered immediately after HI, exhibits neuroprotective properties, and could be a potential pharmacological treatment to prevent the impact of hypoxia on brain function in adults. En la presente tesis, hemos desarrollado un modelo de hipoxia-isquemia (HI) en ratones adultos para estudiar los mecanismos neuroprotectores de los receptores cannabinoides CB2 (CB2R) y los posibles efectos terapéuticos del nuevo agonista de PPAR-α, octadecilpropil sulfamida (SUL). En primer lugar, determinamos las alteraciones conductuales y cognitivas inducidas por HI en ratones knock-out CB2R (KO) y controles (WT), así como las alteraciones celulares y moleculares asociadas con la lesión cerebral. En segundo lugar, evaluamos los efectos de SUL sobre las alteraciones conductuales y cognitivas inducidas por HI y estudiamos los procesos de neurodegeneración y los cambios en la expresión de genes relacionados con los sistemas de neuroinflamación/endocannabinoides en el cerebro en ratones adultos C57BL/6J. Nuestros hallazgos sugieren que CB2R confiere neuroprotección después de HI a través de la modulación de los factores proinflamatorios microgliales, HIF-1α y TIM-3, actuando como un mecanismo de defensa para reducir las alteraciones conductuales posteriores. Por otra parte, demostramos que el potente y estable agonista de PPAR-α SUL, administrado inmediatamente después de HI, exhibe propiedades neuroprotectoras, y podría ser un potencial tratamiento farmacológico para prevenir el impacto de la hipoxia en la función cerebral en adultos.

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49

Abdelrahman, Mostafa Hamed. "Design, synthesis and SAR of novel allosteric modulators of the Cannabinoid CBI receptor." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=159203.

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We report on the design, synthesis, and structure activity relationship studies of novel Org 27569 analogues as potential allosteric modulators of the CB1 receptors. We also investigated by computer modelling the possible location of the allosteric site on CB1 and the binding confirmation of the allosteric ligands. Docking of the synthesised molecules is also performed and the results are compared to the results of the biological bioassays. The synthesis of non-fused indole analogues of Org 27569 is described. These analogues were systematically varied to study the importance of key functional groups for CB1 allosteric activity. It was found that the two NH groups of the indole derivatives are required for activity. Activity is also significantly improved for analogues possessing a hydroxymethyl group or a hydrophobic chain at position 3 of the indole moiety. SAR analysis also shows that the presence of a dialkylamino group at the para-position on the aromatic side chain further improves the activity. Conformationally restricted analogues (fused indoles) of Org 27569 were prepared to determine the possible binding conformation of Org 27569. An analogue having the two NH groups directed in the same direction exhibited a moderate ability to enhance CP55,940 affinity and gave significant decrease in [35S]GTPγS binding at 1μM, indicating the possible binding conformation for the Organon derivatives. Molecular modelling studies allowed locating a possible binding pocket for the CB1 allosteric ligands. The study described here should help the design of ligands of the CB1 allosteric site that possess higher biological activities and specificities. The results should pave the way for the discovery of the anti-obesity drugs of the future.

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50

Yates, Andrew Stephen. "Fluorescent cannabinoids : strategies towards the synthesis of fluorescently labelled CB2 receptor ligands." Thesis, University of Nottingham, 2005. http://eprints.nottingham.ac.uk/10107/.

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An increased understanding of the peripheral cannabinoid receptor (CB2) is required due to the CB2 receptor's emerging involvement in a number of disease states. New fluorescent technologies are capable of generating information about the CB2 receptor systems that has been unachievable using existing pharmacological methods i.e. radioisotope techniques. Our work, to develop fluorescently labelled CB2 receptor ligands, will provide cannabis researchers a unique pharmacological tool to use in conjunction with these emerging fluorescent technologies. This will aid the understanding of cellular actions of cannabinoids and accelerate the discovery of novel CB2 selective drugs. We report on the design, synthesis, and biological evaluation of novel fluorescent ligands targeted towards the CB2 receptor. The fluorescent ligands were designed and synthesised by conjugating recognized high affinity selective CB2 ligands (JTE2-3, JTE2-6 & JWH015) to appropriate fluorescent dyes via a chemical linker. Positioning of the fluorescent dye upon the pharmacophore was guided using established SAR data and supplemented by in-house molecular modelling experiments. Our results showed that modification of JTE2-3 and JTE2-6 with dansyl and BODIPY fluorophores resulted in fluorescent ligands which displayed poor affinity to the CB2 receptor and consequently were unsuccessful when used in fluorescent confocal microscopy experiments. Furthermore, our studies revealed important species selectivity, associated with JTE2-3, which was previously unrecognised. Using de novo drug design on JWH015, we synthesised and tested a 3-naphthyl modified fluorescent conjugate, 3-Gly-NBD-JWH015. The compound retained limited affinity to the CB2 receptor, but fluorescent confocal microscopy did not reveal specific receptor membrane binding. Further experiments using 3-naphthyl precursor compounds, displaying less bulky 3-substituents, demonstrated that limited modification to the 3-naphthyl position of JWH015 was tolerated and provided a first insight to the SAR at this position.

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