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1
Goonawardena, Anushka V. "Cannabinoid effects on hippocampal neurophysiology and mnemonic processing." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources. Restricted: no access until Mar. 17, 2011, 2008. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=26047.
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Whyte, Lauren Sarah. "Molecular pharmocology of cannabinoids and the novel cannabinoid receptor GPR55 in bone." Thesis, University of Aberdeen, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=103940.
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Given the recent finding that the cannabinoid receptors CB1 and CB2 affect bone metabolism, we examined the role of GPR55 in bone biology. GPR55 was expressed in human and mouse osteoclasts and osteoblasts; expression was higher in human osteoclasts than in macrophage progenitors. Although the GPR55 agonists O-1602 and LPI inhibited mouse osteoclast formation in vitro, these ligands stimulated mouse and human osteoclast polarisation and resorption in vitro and caused activation of Rho and ERK1/2. These stimulatory effects on osteoclast function were attenuated in osteoclasts generated from GPR55-/- macrophages and by the GPR55 antagonist cannabidiol (CBD). Furthermore, treatment of mice with this non-psychoactive constituent of cannabis significantly reduced bone resorption in vivo. Consistent with the ability of GPR55 to suppress osteoclast formation but stimulate osteoclast function, histomorphometric and microcomputed tomographic analysis of the long bones from male GPR55-/- mice revealed increased numbers of morphologically-inactive osteoblasts, but a significant increase in the volume and thickness of trabecular bone and the presence of unresorbed cartilage. These data reveal a hitherto unrecognised role of GPR55 in bone physiology by regulating osteoclast number and function. In addition, this study also brings to light a newly identified effect of both the endogenous ligand, LPI , on osteoclasts and of the cannabis constituent, CBD, on osteoclasts and bone turnover in vivo. These results suggest that blocking GPR55 with small molecules similar to CBD may be beneficial in bone diseases associated with increased osteoclast activity such as osteoporosis.
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Li, Yan. "THE ROLE OF CANNABINOIDS AND CANNABINOID RECEPTORS IN ENTERIC NEURONAL SURVIVAL." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1947.
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The Endocannabinoid system has been found in the gastrointestinal tract, where it plays an important role in gut under both physiological and pathological conditions. Although the major effects of cannabinoids in the gut are mediated through effects on enteric neurons, the role of cannabinoids in the enteric nervous system is poorly understood. In the present study, we have used the primary cultures of myenteric ganglia and a newly developed fetal enteric neuronal cell line to identify whether the endocannabinoid, anandamide, affects ganglionic and neuronal survival and the pathways involved. Anandamide had a biphasic effect on ganglionic survival, increasing survival at low concentrations (1nM-0.1uM) and decreasing survival at high concentrations (1-10uM). Maximal survival (68% increase in number of ganglia surviving) occurred at 0.1uM and the ED50 was 3nM. This effect on promoting survival was inhibited by the CB1 antagonist AM251 (1uM) and by AraC (10uM), but not the CB2 antagonist AM630 (1uM). AM630 (1uM) significantly blocked the decreased survival induced by high concentration anandamide (10uM). The enteric glia was involved in anandamide-induced ganglion survival. Anandamide had no effect on the number of neurons/ganglion in the presence of enteric glia, but decreased the number of neurons/ganglion by 15-20% in absence of enteric glia. This effect was partially reversed by CB1 antagonist, AM251 (1uM) (20%-145% at 1nM-10uM) and by CB2 antagonist AM630 (1uM) (40%-185% at 1nM-10uM). In the fetal enteric neural cell line (IM-FEN), anandamide decreased enteric neuronal survival in a concentration-dependent manner at both 39 and 33 degree (11-45% and 10-22%decrease in survival at 1nM-10uM, respectively). Coculture of astrocytes with the enteric neuronal cells was not able to reverse anandamide-mediated neuronal death. Immunocytochemistry and western blot confirmed that the presence of both CB1 and CB2 receptors in enteric neurons (primary cultures and IM-FEN) and glia (primary cultures). In addition, the PLC-beta inhibitor U73122 (1uM) inhibited anandamide induced ganglia survival significantly. Anandamide also induced increased expression of phospho-P44/42MAPK (13-48% at 1nM-10uM) and phospho-AKT (1-28% at 1 nM-10uM) in IM-FEN. We conclude that anandamide has a differential effect on survival of enteric ganglia and neurons. It promotes ganglionic and neuronal survival by CB1 receptors in the presence of glia and this involves the PLC-beta pathway. Conversely, anandamide promotes neuron death in absence of glia as a result of effects on both the MAPK and PI-3K/AKT pathways. Since the endocannabinoid system is upregulated in inflammatory bowel diseases, these effects may play a role in the pathogenesis of the response to inflammation as well as the recovery and reinnervation of the gut following the acute phase of inflammation. The further significance of this work could contribute to developing new therapeutic methods for treatment of inflammatory bowel disease and related symptoms in clinic practice.
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Firth, D. F. "Cannabinoids and cembranoids." Thesis, University of Nottingham, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380140.
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Habayeb, Osama. "Cannabinoids and reproduction." Thesis, University of Leicester, 2009. http://hdl.handle.net/2381/29866.
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The success of implantation depends on the synchronous development of the embryo and the endometrium. This process is recognised to be regulated by the endocannabinoid system, the most widely studied of which is anandamide.;The first part of this study was the development of a robust assay to measure anandamide in human plasma. The assay was then applied to measure anandamide concentrations during the menstrual cycle, pregnancy, labour and in a group of women presenting with threatened miscarriage. The mean plasma anandamide levels in the follicular phase were 1.68 nM compared to 0.87 in the luteal phase. In pregnancy, the mean levels in the first trimester were 0.89 nM and 0.44 in both the second and third trimesters. At term, the mean levels were 0.68 in the non-labour group and to 2.5 nM in labour. In the threatened miscarriage group, anandamide levels >2.0 nM were predictive of subsequent miscarriage with sensitivity of 100%, specificity of 94.4%, negative predictive value of 100% and positive predictive value of 81.8%.;Finally, to try and identify potential targets of anandamide action, the expression of the cannabinoid receptors (CB1 & CB2) and the enzyme FAAH was studied in first trimester placentas. All proteins studied were present in the tissues examined with the expression of the CB1 diminishing after 9 weeks and FAAH disappearing by 11 weeks gestation. Similarly, anandamide inhibited the growth of BeWo cells in culture. Taken together, these findings suggest that anandamide plays a role in the maintenance of early pregnancy.
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Nilsson, Olov. "Cannabinoids as neuroprotective agents : a mechanistic study." Doctoral thesis, Umeå : Umeå universitet, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-873.
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Brown, Nigel Kenneth. "Metabolism of the cannabinoids." Thesis, University of Oxford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236245.
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Dudasova, Anita. "Cannabinoids and bronchial airways." Thesis, University of Hertfordshire, 2009. http://hdl.handle.net/2299/3638.
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Although there is a renewed interest in the therapeutic potential of cannabinoids, pharmacological and physiological characterisation of these promising compounds is currently not well documented in the respiratory system. The aim of this study is to increase our understanding of possible roles of cannabinoids in the airways. Apart from CB1 and CB2 receptor-mediated actions, cannabinoid compounds can also target TRPV1 receptors, ion channels or the orphan GPR55. In isolated guinea-pig bronchi, WIN55212-2 probably exerted its inhibitory effect on sensory nerves through CB2-like receptors. VIR did not act prejunctionally but its excitatory action was mediated through TRPV1 receptors. Δ9-THC activated sensory nerves presumably involving CB1 receptors. It was speculated that GPR55 might be activated by VIR and antagonized by CBD. CBD revealed multiple mechanisms of actions: it antagonized effects mediated by TRPV1 and NK2 receptors, modulated mast cell function and showed anti-allergic activity in an in vitro model of bronchial asthma. In a human bronchial epithelial cell line the functional expression of CB1 receptors could not be confirmed. Cannabinoids examined in this study were ineffective to induce signal transduction which would be linked to ion channel activity or to intracellular Ca2+ changes. Only VIR might trigger a CB1 receptor-independent signalling pathway in these cells. In conclusion, the findings presented in this thesis reflect the diversity of cannabinoid pharmacology in the airways. They show for the first time that CBD has the ability to reduce antigen-induced bronchoconstriction, indicating relevance in bronchial asthma.
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Sun, Yan. "Cannabinoids and PPARa signalling." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431260.
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Casey, Sherelle. "Cannabinoids for Neuropathic Pain." Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/24007.
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Neuropathic pain is a severe chronic syndrome and is poorly served by current pharmacotherapeutics. There is some evidence that the cannabis constituents tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination relieves neuropathic pain. However, there is little to no animal evidence for their effectiveness and side effects in neuropathic pain models. In this thesis, a systematic analysis of THC and CBD was performed in a mouse neuropathic pain model. Systemic subcutaneous and oral THC had high anti-allodynic efficacy, but was accompanied by side effects. By contrast, CBD had lower anti-allodynic efficacy, but lacked side effects. Isobolographic analysis demonstrated synergistic analgesia for combination THC and CBD for subcutaneous but not oral administration. Thus, combination THC:CBD had a high therapeutic window when delivered subcutaneously but not orally. Finally, both THC and CBD produced high efficacy anti-allodynia without side effects administered via intrathecal or intraplantar injection. The actions of THC were mostly cannabinoid CB1 receptor mediated, while the actions of CBD were not cannabinoid receptor mediated. An in vitro electrophysiological identified potential cannabinoid targets in sensory neurons. Activity at T-type calcium currents, but not other calcium currents or tetrodotoxin-resistant sodium currents, may account for some of the anti-allodynic activity of THC and CBD. Overall, this thesis provides pre-clinical evidence that the phytocannabinoids THC and CBD alone may be useful as an adjunct therapy for treatment of neuropathic pain, and provides insight as to the ideal ratio and differing benefits and challenges of different administration routes. It also provides some insight into the cellular mechanisms of activity of these phytocannabinoids.
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Ryberg, Erik. "GPR55 : a novel cannabinoid receptor." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=61555.
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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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DI, FELICIANTONIO MARINA. "Studio in vitro sulla stabilità strutturale dei cannabinoidi sintetici nel fluido orale." Doctoral thesis, Università Politecnica delle Marche, 2018. http://hdl.handle.net/11566/253005.
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Nell’ultimo decennio il mercato clandestino delle droghe d’abuso ha visto la nascita,
prima, e l’affermazione, poi, di sostanze sintetiche molto più pericolose delle droghe
tradizionali. Nel 2012 la Commission on Narcotic Drugs le ha classificate con il
termine di NPS o “Nuove Sostanze Psicoattive”, legalmente commercializzate come
profumatori ambientali denominati “Spice”. Risultati chimico-tossicologici hanno
evidenziato la presenza, in questi prodotti, di cannabinoidi sintetici particolarmente
affini ai recettori dei cannabinoidi CB1.
Obiettivo della Ricerca è stato quello di valutare la stabilità strutturale di queste
molecole quando sottoposte ad un cambiamento dello stato fisico dovuto alle alte
temperature raggiunte durante il processo di fumo. L’attenzione è stata richiamata
dalla saliva, matrice biologica immediatamente interessata nel processo di fumo,
caratterizzata da prelievo non invasivo e che ha permesso l’ottenimento di dati certi e
ripetibili in spettrometria di massa ad alta risoluzione. La struttura altamente
lipofilica delle molecole impone l’uso di contenitori in vetro, al fine di evitarne
l’adsorbimento sulla superficie delle provette in polipropilene, mentre la temperatura
di conservazione a cui è sottoposta la matrice biologica influisce sulla potenziale
degradazione dei cannabinoidi sintetici ad opera degli enzimi salivari e/o microbici. I
risultati ottenuti evidenziano una stabilità strutturale certa delle molecole sottoposte
ad indagine, ma il dato analitico ottenuto, utilizzabile sia in ambito clinico che
forense, deve rispettare un rigido protocollo analitico/strumentale.In the last decade the illegal drug market has seen the birth, first, and the affirmation, then, of synthetic substances much more dangerous than traditional drugs. In 2012 the Commission on Narcotic Drugs classified them under the term NPS or "New Psychoactive Substances", legally marketed as environmental fragrances named "Spice". Chemical-toxicological results have highlighted the presence, in this products, of synthetic cannabinoids particularly affine to CB1 cannabinoid receptors. The aim of the research was to evaluate the structural stability of these molecules when subjected to a change of the physical state due to the high temperatures reached during the smoking process. The attention was drawn to saliva, the biological matrix immediately involved in the smoking process, characterized by non-invasive sampling and which allowed obtaining reliable and repeatable data in high-resolution mass spectrometry. The highly lipophilic structure of the molecules requires the use of glass containers, in order to avoid adsorption on the surface of polypropylene tubes, while the storage temperature to which the biological matrix is subjected influences the potential degradation of synthetic cannabinoids by salivary and/or microbial enzymes. The results obtained show a certain structural stability of the molecules under investigation, but the analytical data obtained, usable both in the clinical and forensic field, must comply with a strict analytical/instrumental protocol.
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Bambico, Francis. "Cannabinoids and Endocannabinoids in mood regulation." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=95031.
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Cannabinoids (CB) are compounds structurally derived from Δ(9)-THC, the main pharmacologically active component of cannabis and marijuana. CBs produce psychoactive effects by binding the cerebral CB1 receptor (CB1R). The mammalian brain also naturally produces endocannabinoids (eCBs), intrinsic ligands of CB1R. At the start of this doctoral project, the role of the eCB system in mood regulation and the interaction between CBs and monoamines remained largely unexplored. The main aim of this project was to characterize the effects of CBs and eCBs on depression-like reactivity in murids. Since serotonin (5-HT) and norepinephrine (NE) are the major monoamine neurotransmitters implicated in depression pathophysiology and in the mechanism of action of antidepressants, we employed electrophysiological techniques to assess the in vivo effect of CBs and eCBs on 5-HT neurons of the dorsal raphe, on NE neurons of the locus coeruleus, and on postsynaptic limbic areas. The direct CB1R agonist WIN55,212-2 produced a bell-shaped effect in the rat forced swim test (FST), with low doses eliciting antidepressant-like activity while high doses being inert. This behavioural pattern was congruent with electrophysiological data. Indeed, a rapid increase of 5-HT neural activity was observed at low-doses while an attenuation below basal levels was observed at high doses. The enhanced 5-HT activity was instigated by an excitatory feedback driven by CB1Rs in the ventromedial prefrontal cortex, a limbic structure involved in stress controllability. Chronic exposure to low or high doses of WIN55,212-2 in adolescence but not in adulthood precipitated depressive- and anxiety-like reactivity that persisted in adulthood. These emotional impairments were associated with 5-HT hypoactivity and NE hyperactivity. URB597 is a novel compound that inhibits fatty acid amide hydrolase (FAAH), an enzyme that degrades anandamide, one of the major eCBs. URB597 is thus able to markedly enhance brain anandaLes cannabinoïdes (CBs) sont des composés dérivés structurellement du Δ(9)-THC, le principe actif du cannabis. Ces drogues produisent leurs effets en se liant aux récepteurs CB1 (CB1R). Le cerveau produit également des endocannabinoïdes (eCBs) naturellement, et ceux-ci constituent les ligands intrinsèques du CB1R. Le rôle du système eCB dans la régulation de l'humeur et l'interaction entre les CBs et les monoamines étaient des sujets encore largement inexplorés. L'objectif était de caractériser l'impact de la modulation du système eCB par les CBs/eCBs sur des modèles de dépression chez le rongeur. Comme la sérotonine (5-HT) et la norépinéphrine (NE) sont les neurotransmetteurs impliqués dans la pathophysiologie et le traitement de la dépression, nous avons utilisé des techniques électrophysiologiques pour isoler in vivo l'effet des CBs/eCBs sur l'activité neurones 5-HT du raphé dorsal, des neurones NE du locus coeruleus et sur les aires postsynaptiques du système limbique. L'agoniste du CB1R, le WIN55,212-2, produit un effet bi-phasique lors du test de nage forcée (FST). Les faibles doses ont entraîné une réponse de type anti-dépresseur, alors que les doses élevées sont restées sans effet. La modulation de la 5-HT a également montré une réponse bidirectionnelle, les faibles doses ayant stimulé l'activité neuronale 5-HT, et les doses élevées la réduisant sous le niveaude base. L'augmentation de l'activité 5-HT semble mettre en action une boucle excitatrice engendrée par la stimulation des CB1R du cortex préfrontal ventromédial, qui est impliqué dans le contrôle du stress. À l'adolescence, l'exposition chronique au WIN55,212-2, a engendré une perturbation semblable à la dépression et l'anxiété qui persiste à l'âge adulte. Ces troubles émotionnels semblent être associés à une hypoactivité de la 5-HT et à une hyperactivité de la NE. L'URB597 est un composé inhibant l'acide gras amide hydrolase (HAAG),
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Morrison, Paul D. "Cannabinoids and psychosis : cause and treatment." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/cannabinoids-and-psychosis--cause-and-treatment(8866b980-8ef1-49d8-ae76-e340b9d8c57f).html.
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Epidemiological studies suggest that cannabis is a risk factor for psychotic illness. The main active ingredient is Δ-9-Tetrahydrocannabinol (THC). In healthy humans, the acute administration of THC can elicit transient psychotic symptoms and cognitive impairment. THC stimulates the endocanabinoid CB1 receptor (CB1R). However, beyond CB1Rs, the mechanism underlying the pro-psychotic effects of THC is unknown. The ecploration of candidate mechanisms was the first major theme in this thesis. In Study 1 the pro-psychotic properties of intravenous (IV) THC were confirmed. Thereafter, studies 2and 3 explored whether the pro-psychotic effects were related to excess striatal dopamine release or abnormal neural oscillations respectively. The cannabis plant contains over sixty cannabinoid molecules, one of which, Cannabidiol (CBD) can antagonise some of the pharmacological effects of THC. It has been suggested that the absence of CBD in modern, 'high-potency' forms of cannabis (sinsemilla or 'skunk') underlies the risk of such preparations for mental health. However, the evidence for this is sparse. Characterising the effect of CBD on THC-elicited responses was the second major theme in this thesis. Studies 4 and 5 tested whether CBD inhibited acute THC elicited psychosis. In study 1 the psychotomimetic effects of acute IV THC were confirmed. THC-elicited positive symptoms were distinct from anxiety, and negative symptoms were distinct from sedation. Cognitive performance was impaired under THC conditions. In study 2, THC had no significant effect on striatal dopamine release despite inducing robust positive psychotic symptoms. In study 3, THC-elicited positive psychotic symptoms were related to reduced bi-frontal coherence in the theta (4-8Hz) band. Studies 4 and 5 both showed that CBD pre-treatment inhibits acute THC-elicited psychosis. Overall two major findings emerged. 1. The pro-psychotic effects of THC were related to abnormal neural oscillations, but not to striatal dopamine release; 2. Cannabidiol inhibits acute THC psychosis.
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Kevin, Richard Charles. "The Psychopharmacology of Novel Synthetic Cannabinoids." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17613.
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Over recent years, the rapid proliferation of novel psychoactive substances has presented significant challenges to health professionals, regulators, and forensic scientists alike. Synthetic cannabinoids comprise an increasingly prevalent and diverse class of compounds that are used by many people around the world for recreational purposes. These compounds tend to produce psychoactive effects similar to, but stronger than, those of the prototypical cannabis-derived receptor agonist ∆9-tetrahydrocannabinol. The majority of modern synthetic cannabinoids have never been systematically assessed for their effects in humans, meaning that their psychopharmacological and toxicological effects remain largely uncharacterised. Unfortunately, but perhaps not surprisingly, these compounds are implicated in scores of toxic and fatal episodes worldwide. This thesis presents a series of studies aimed at building new knowledge regarding the behavioural and physiological effects of specific synthetic cannabinoids, their potency and metabolism, their long-term effects on cognitive function and brain neurochemistry, and analytical techniques that may be useful in the development of agonist substitution therapies to assist with synthetic cannabinoid withdrawal. The results obtained in this thesis and the wider literature are combined to identify in vivo structure-activity and structure-metabolism relationships for a wide variety of synthetic cannabinoids. These relationships may prove useful for the prediction of the psychopharmacological properties and metabolic pathways of future novel synthetic cannabinoids, reducing the burden involved in testing large numbers of novel compounds individually. Based on rodent assays, long-lasting cognitive impairments and subtle biochemical modulations are predicted in chronic synthetic cannabinoid users. Finally, analytical techniques for evaluating and monitoring agonist replacement therapy for synthetic cannabinoid withdrawal are established.
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Morefield, Samantha I. (Samantha Irene). "Responses of Cultured Neuronal Networks to the Cannabinoid Mimetic Anandamide." Thesis, University of North Texas, 1998. https://digital.library.unt.edu/ark:/67531/metadc277717/.
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The effects of cannabinoid agonists on spontaneous neuronal network activity were characterized in murine spinal cord and auditory cortical cultures with multichannel extracellular recording using photoetched electrode arrays. Different cultures responded reproducibly with global decreases of spiking and bursting to anandamide and methanandamide, but each agonist showed unique minor effects on network activity. The two tissues responded in a tissue-specific manner. Spontaneous activity in spinal tissue was terminated by 1 μM anandamide and 6.1 μM methanandamide. Cortical activity ceased at 3.5 μM and 2.8 μM respectively. Irreversible cessation of activity was observed beyond 8 μM for both tissues and test substances. Palmitoylethanolamide, demonstrated that CB2 receptors were not present or not responsive. However, the data strongly suggested the presence of CB1 receptors.
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Whiting, Penny F., Robert F. Wolff, Sohan Deshpande, Nisio Marcello Di, Steven Duffy, Adrian V. Hernández, J. Christiaan Keurentjes, et al. "Cannabinoids for Medical Use A Systematic Review and Meta-analysis." American Medical Association, 2015. http://hdl.handle.net/10757/558499.
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Importance Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear.
Objective To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids.
Data Sources Twenty-eight databases from inception to April 2015.
Study Selection Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome.
Data Extraction and Synthesis Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis.
Main Outcomes and Measures Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs.
Results A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, −0.36 [95% CI, −0.69 to −0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.
Conclusions and Relevance There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.
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Arnold, Jonathon C. "The behavioural and neural effects of cannabinoids studies using Lewis and Wistar strain rats /." Connect to full text, 2000. http://hdl.handle.net/2123/364.
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Thesis (Ph. D.)--University of Sydney, 2001.Title from title screen (viewed Apr. 22, 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Dept. of Psychology, Faculty of Science. Degree awarded 2001; thesis submitted 2000. Includes bibliography. Also available in print form.
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Kinden, Renee. "Cannabinoids & Stress: The Impact of Endogenous and Exogenous Cannabinoids on Anxiety Behaviors In an Acute Stress Model." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32784.
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Although the impact of cannabinoids (CBs) on anxiety has been thoroughly studied, current research paradigms fail to incorporate acute stressors. The present study investigated the synthetic CB HU-210’s anxiolytic potential in an acute stress CD1 male mouse model, where the animals were subject to a 10-minute Forced Swimming (FS) test between treatment and behavioral tests. Surprisingly, HU-210 did not show anxiolytic action in the Open Field (OFT) and Elevated-Plus Maze (EPM) stressed mice as previously reported in the naïve model literature. The combination of acute stress and high HU-210 doses produced severe locomotor impairments in ambulatory movement that were not previously observed in unstressed mice. It is hypothesized that this anxiogenic phenotype results from the summation of exogenous CB treatment and stress-induced endocannabinoid (eCB) release.
Subsequently, the impact of the eCB signaling on anxiety behaviors was examined. Systemic administration of KML29, the selective inhibitor of 2-AG degradative enzyme, returned stress-induced anxiety-like behaviors to baseline levels, without significantly affecting locomotion. KML29’s anxiolyticism was abolished when combined with the cannabinoid receptor antagonist AM281, implying this is a CB receptor-mediated process. A GABAA receptor agonist muscimol was co-administered with KML29 in order to pharmacologically investigate the role of GABAergic neurotransmission in this anxiolytic phenomenon, but it did not alter KML29’s effects.
Collectively, these findings suggest that exogenous CBs and acute stress act synergistically in an anxiogenic manner, but that enhanced 2-AG signaling in response to stress demonstrates anxiolytic potential.
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Khalid, Aysha Binty. "Regulation of bone by cannabinoid and cannabinoid-like receptors." Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=202765.
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Bone is a dynamic living organ that differentiates vertebrates from other animals. Calcification makes the tissue dense, stiff, strong and careful control of the material and geometrical properties of bone attempts to match their properties to the prevailing mechanical environment. Bone homeostasis involves an array of factors, only a few of which are known. The cells that produce bone, osteoblasts, share a common origin with adipocytes in mesenchymal stem cells (MSC) and there is mounting evidence of dysregulation of MSC differentiation in bone disorders such as osteoarthritis and osteoporosis. The cannabinoid system has recently been shown to be involved in bone homeostasis and has been proposed as a potential therapeutic target for treatment of bone diseases. However studies published to date look almost exclusively at its effect on trabecular bone. A full understanding of any regulatory factor can come only by considering both cortical and trabecular bone. This thesis describes experiments to characterize the mechanical, material and geometrical properties of cortical and trabecular bone from mice in which cannabinoid, CB1, CB2, or putative cannabinoid, GPR55, receptors have been deleted. Further studies started to explore the biological basis underlying the role of GPR55 and one of its antagonists, cannabidiol (CBD). The hypothesis was that endogenous cannabinoids can regulate bone properties and the aim Abstract ii was to resolve discrepancies found in previous studies and begin to explore the effect of cannabidiol acting through the GPR55 receptor on MSC differentiation. CB1 -/- mice had inferior mechanical properties to wild type mice due to reduced geometrical properties while the material properties remained unchanged. No change was found in trabecular bone volume in males but female CB1 -/- mice showed a high bone mass phenotype. CB2 -/- mice had mechanically superior bones to wild type animals due to larger geometrical properties. These superior characteristics were also seen in trabecular bone, where the female KOs had a high bone mass phenotype. The effect of knocking out GPR55 showed an increase in the amount of both cortical and trabecular bone. The knockout mice were fatter and were protected against age related bone loss. In addition, CBD enhanced adipogenesis in both humans and mice, while no effects were seen on osteogenesis. Enhanced adipogenesis was also found in GPR55-/- cell cultures. These results suggest that blocking GPR55 with small molecules such as CBD may be beneficial in bone diseases such as osteoporosis but not osteoarthritis.
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Anderson, Richard L. "The effects of cannabinoids on insulin secretion." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/11760/.
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Type 2 diabetes mellitus is a chronic condition caused by a deficiency in the secretion of insulin from the islets of Langerhans and/or impaired insulin signalling, resulting in hyperglycaemia. The role of the endocannabinoid system is well-recognised in the CNS and immune system, but its role in glucose homeostasis is poorly understood. The aim of this study was to define the roles of cannabinoids in insulin secretion, to provide insights into their therapeutic potential (or limitation) in the treatment of type 2 diabetes. Isolated islets were used, from Wistar rats, in static incubation studies measuring changes in insulin secretion rates. The endocannabinoid anandamide (AEA) was found to inhibit insulin secretion in a glucose- and concentration-dependent manner, with an IC50 of 1.6μM (95% CI: 227nM to 4.0μM; n= 10). Upon further analysis of the concentration-response data islet sensitivity to AEA appeared to vary, with islets either appearing to be sensative (IC50 220nM; 95% CI: 21.9nM to 2.2μM; n= 5) or less sensative (IC50 12.3μM; 95% CI: 6.8μM to 19.4μM; n= 5) to AEA. Pre-incubation of islets with a fatty acid amide hydrolase inhibitor did not affect islet responsiveness to AEA. AEA-mediated inhibition of insulin secretion was not consistently affected by cannabinoid receptor 1 (CB1) or CB2 antagonism. Surprisingly, the CB1 receptor antagonist AM251 was found to inhibit insulin secretion in a glucose- and concentration-dependent (IC50 1.6μM; 95% CI: 507nM to 3.3μM; n= 6) manner. Results from this study suggest that differences in CB-receptor signalling pathways, rather than endocannabinoid metabolism, could be responsible for the variations in the potency of AEA between islet preparations. Characterisation of cannabinoid signalling in islets was hindered as the CB receptor antagonists used in this study also affected insulin secretion. This study highlights the dynamics of endocannabinoid signalling in islets, which may be linked to their physiological function.
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Turner, Richard Vernon. "SYNTHETIC CANNABINOIDS: CHARACTERIZING THEIR USE AND CESSATION." OpenSIUC, 2019. https://opensiuc.lib.siu.edu/dissertations/1766.
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Since their introduction to the United States in 2008, synthetic cannabinoids became the most widely used recreational drug behind marijuana, then regressed to an estimated prevalence of less than 1%. Contrary to expectations for a drug declining in use, emergency department presentations and acute poisonings related to the use of synthetic cannabinoids are increasing. Alongside this phenomenon, a growing body of literature is beginning to uncover a relationship between psychosis and synthetic cannabinoid use. A current gap in the literature exists surrounding harm prevention methods and targeted intervention strategies for users of synthetic cannabinoids. To date, no known studies have examined individuals with a history of use of these substances and investigated the reasons they decided to discontinue recreational use. The purpose of the current study was to fill this gap in the literature while also further confirming and expanding existing research on the characterization of synthetic substance use, perceived harm of synthetic cannabinoids, and users’ knowledge about synthetic cannabinoids. Cross sectional survey methods in a non-experimental comparative design was utilized with participants recruited through the online crowd sourcing platform Amazon MTurk. Significant motivating factors for both discontinuation and continuation of synthetic cannabinoid use were found including personal experience, accessibility, preference towards other substance, and questions surrounding the source and purity of the synthetic cannabinoids. It was also found that individuals who currently use synthetic cannabinoids have less general knowledge about the substance class when compared to individuals who have discontinued use. These results suggest that psychoeducational campaigning surrounding general knowledge about the substance class as well as information on the physiological effects of synthetic cannabinoids may be an effective harm reduction method.
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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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Hake, Mark Lewn. "Marijuana Legalization and Traffic Fatalities Involving Cannabinoids." ScholarWorks, 2019. https://scholarworks.waldenu.edu/dissertations/6330.
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Washington State and Colorado were the first states to legalize recreational marijuana. According to the Washington Traffic Safety Commission, the number of drivers who tested positive for marijuana in traffic fatalities increased 48% from 2013 to 2014, and marijuana legalization may have influenced this increase. Since marijuana legalization is new to the United States, the effects of this change in policy are untested in the literature. The purpose of this quantitative study using a regression point displacement design was to examine the relationship between traffic fatalities involving cannabinoids in Washington State before and after marijuana legalization. Rational choice theory and perceptual deterrence theory provided the framework for the study. Existing state level data of traffic fatalities from the National Highway Traffic Safety Administration's Fatality Analysis Reporting System were analyzed using regression point displacement. Pre and post legalization Washington state fatalities were compared against 43 control groups where marijuana has not been legalized for recreational use. Results from ANCOVA analysis indicated no statistical difference between Washington State and other nonlegalized states in traffic fatalities involving cannabinoids. This is one of the first studies exploring the effects of marijuana legalization on public safety. These results suggest marijuana legalization may not contribute to the increase in traffic fatalities. Findings may provide legislators and traffic safety stakeholders with information in creating legislation legalizing marijuana as well as strategy and a research agenda to address traffic fatalities.
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Ford, Lesley. "The pharmacology of GPR55 and its potential role in cancer." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources. Restricted; no access until Jan. 1, 2015, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=59625.
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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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Sherer, Jennifer. "Gender differences in the cardiovascular effects of cannabinoids." Thesis, University of Strathclyde, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501827.
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Gender has been shown to influence the effect of cannabinoids on vascular tone in vitro and cannabinoid metabolism by platelets. The current study examined the influence of gender on the in vivo cardiovascular effects of the cannabinoids and their effect on platelet aggregation. Method and Results: Age-matched anaesthetised male (400-500g) and female (275-290g) rats were treated with anandamide, 1 mg/kg and 3 mg/kg, and HU-21 0, 0.03 ug/kg and 0.1 ug/kg, and changes in heart rate and blood pressure were measured. Anandamide and HU-210 produced hypotension with a greater hypotensive response in male rats compared to females, whereas greater bradycardia in response to anandamide was observed in female rats. Whole blood aggregometry studies were performed in arterial blood taken from male and female rats to examine the aggregatory effects of2-AG, 75 uM, 150 uM and 300 uM and the interaction with 5-HT 10 uM and ADP 1 uM. 2-AG produced concentration- dependent aggregation which was potentiated by 5-HT with a greater response to the lower 2-AG concentration and potentiation by 5-HT in male rats. 2-AG resulted in similar potentiation and prolongation of the response to ADP in male and female rats. The study also examined the effect of the CB I and CB2 antagonists, AM251 and , AM630, on ADP-induced aggregation and it was shown that these receptors are not involved in this aggregation response. Conclusion: The haemodynamic and platelet aggregatory effects of cannabinoids may be influenced by gender. The mechanisms which mediate these gender differences-are yet to be identified.
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Pryce, Gareth. "Cannabinoids for the control of experimental multiple sclerosis." Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/673.
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There have been numerous studies reporting that cannabinoids, both exogenous and endogenous, have a potential beneficial function during incidences of neurological damage. Using gene knockout mice and cannabinoid-selective agents, this study demonstrates the diverse actions of cannabinoids with a particular focus on experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. The results presented here report on the action of stimulators of cannabinoid receptors in the nervous system (CNS) on; immune function, as a mechanism of suppressing autoimmune attack of the central nervous system, as agents to suppress neurodegenerative events leading to disease progression and as agents that can control signs of disease that occur as the consequences of autoimmune neurodegeneration such as spasticity. Tetrahydrocannabinol the psychoactive component in cannabis and the CB1 cannabinoid receptor appears to be central to many of the therapeutic actions of cannabis but also to the side-effect potential of cannabinoid drugs. This study reports on methods to avoid psychoactive side-effects of conventional brain-penetrant CB1 receptor agonists whilst exploiting the therapeutic potential of the cannabinoid system in order to control spasticity. This was achieved by targeting mechanisms of endocannabinoid degradation, particularly using fatty acid amide hydrolase inhibitors. Furthermore, this study also reports the development of novel cannabinoid compounds that are excluded from the brain and inhibit spasticity and also demonstrates the mechanism of exclusion of CNS-excluded cannabinoid CB1 receptor agonists. This study provides further evidence for the efficacy of cannabinoid compounds during an ongoing CNS disease and also their efficacy for treating the consequences of CNS autoimmune disease, which hopefully, will give additional impetus for further clinical investigations of cannabinoid agents in not only multiple sclerosis but also other neurodegenerative diseases of the CNS.
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Amos, D. P. "Effects of cannabinoids and novelty on hippocampal electrophysiology." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1335611/.
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Exposure to novel environments alters hippocampal cell and theta local field potential activity to support the formation of new or updated spatial representations. It induces remapping of place cell fields, a reduction in CA1 theta frequency and an increase in the spatial scale of entorhinal grid cell fields. A recent model proposes that a reduction in the slope of the theta frequency-running speed relationship (TFRSR) can account for these effects (Burgess, 2008, Hippocampus). In contrast, the model proposes that the Y-axis intercept of the TFRSR is unaffected by novelty but instead correlates with anxiety/arousal. Thus, the theta frequency reduction elicited by a wide range of anxiolytic drugs (Gray & McNaughton, 2000) is suggested to result from a decrease in the intercept. Cannabinoids are anxiolytic at low doses, reduce theta frequency and disrupt the theta-timescale dynamics of place cell firing. In contrast, environmental novelty elicits a coordinated shift in CA1 place cell firing to a later theta-phase. This thesis examines the electrophysiological effects of environmental familiarity or novelty in combination with a low, intraperitoneal dose of the cannabinoid agonist O-2545, or its vehicle, saline. It was found that exposure to novel environments reduced the slope of the TFRSR whereas the cannabinoid reduced the intercept, in agreement with the model. These effects were not due to decreased body temperature or changes in behaviour. Combining novelty and drug reduced both slope and intercept. Furthermore, the extent of novelty-induced place cell remapping correlated with the reduction in slope. The mean theta-phase of place cell firing shifted later in novelty, but this was disrupted by the cannabinoid. In contrast, the mean theta-phase of the interneuron population was stable across conditions, but novelty increased the dispersion of interneuron theta-phase preferences. These results help to elucidate the mechanisms underlying novelty processing and cannabinoid action in the hippocampus.
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Jackson, Samuel James. "Cannabinoids and neuroprotection in mouse models of demyelination." Thesis, University College London (University of London), 2004. http://discovery.ucl.ac.uk/1446671/.
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The symptoms of multiple sclerosis (MS), an immune-mediated, degenerative disease of the central nervous system (CNS), are thought to be due to demyelination and axonal damage leading to impairment of neurotransmission. In a mouse model of MS, chronic relapsing experimental allergic encephalomyelitis (CREAE), cannabinoid compounds have been shown to protect axons and improve disease severity. In this study, CREAE and rotation-mediated CNS aggregate cell cultures were used to examine the role of cannabinoid receptor 1 (CB1R) in endocannabinoid-mediated modulation of demyelination and neurodegeneration. The aggregate cell culture system was developed and characterised in mouse to exploit CB1R knockout (CB1R-KO) animals. CREAE was induced in CB1R-KO mice and wildtype counterparts, and CNS aggregate cell cultures derived from the same mouse strains were demyelinated with interferon gamma. CREAE animals were assessed for functional deficit by clinical scoring and in an open field activity chamber. CREAE spinal cords and aggregate samples were assessed for myelin content and axonal damage by measurement of myelin basic protein and neurofilament. Axonal vulnerability was assessed using a monoclonal antibody (SMI-32) against a dephosphorylated neurofilament epitope and caspase 3 expression and activation were measured to gauge cell death. Neurofilament loss following demyelination was increased in CB1R-KO animals and cultures when compared with wildtypes while myelin levels did not differ between the two strains. This indicates that the presence of CB1R may be partially responsible for restricting damage to axons in inflammation, but has a less marked effect on myelination or remyelination. Neurofilament loss correlated with functional deficit, suggesting that axonal or neuronal loss was responsible for neurodegeneration in CREAE. SMI-32 immunoreactivity was also increased, indicating axonal vulnerability or damage through alteration of neurofilament phosphorylation state. Increased activation of caspase 3 in knockout animals and cultures was evident, but not accompanied by increased procaspase 3 expression, signifying higher caspase activation rates. Caspases may therefore be involved in the death of neurons or axonal compromise in these two models. Manipulation of the cannabinoid pathway by exogenous agonist-mediated CB1R activation or indirect upregulation of endogenous ligands could slow disease progression in demyelinating diseases such as multiple sclerosis, indicating a potential therapeutic benefit.
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Costa, Lia Filipa Alvarez Pereira da Mota e. "Cannabinoids impact on pregnancy: effects in trophoblast cells." Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/15948.
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Mestrado em Biologia Molecular e CelularCannabinoids (CBs) can be classified as: phytocannabinoids, the constituents of the Cannabis sativa plant; synthetic cannabinoids lab-synthesized and the endocannabinoids that are endogenous lipid mediators. Cannabinoid compounds activate cannabinoid receptors – CB1 and CB2. The most prevalent psychoactive phytocannabinoid is Δ9tetrahydrocannabinol (THC), but more than 60 different CBs were already identified in the plant. The best characterized endocannabinoids (eCBs) are anandamide (AEA) and 2arachidonoylglycerol (2-AG), that are involved in several physiological processes including synaptic plasticity, pain modulation, energy homeostasis and reproduction. On the other hand, some synthetic cannabinoids that were initially designed for medical research, are now used as drugs of abuse. During the period of placental development, highly dynamic processes of remodeling occur, involving proliferation, apoptosis, differentiation and invasion of trophoblasts. It is known that a tight control of eCBs levels is required for normal pregnancy progression and that eCBs are involved in trophoblast cells turnover. Therefore, by sharing activation of the same receptors, exposure to exocannabinoids either by recreational or medicinal use may lead to alterations in the eCBs levels and in the endocannabinoid system homeostasis In this work, it was studied the impact of CBs in BeWo trophoblastic cells and in primary cultures of human cytotrophoblasts. Cells were treated for 24 hours with different concentrations of THC, the synthetic cannabinoid WIN‐55,212 (WIN) and 2-AG. Treatment with THC did not affect BeWo cells viability while WIN and 2-AG caused a dose-dependent viability loss. Morphological studies together with biochemical markers indicate that 2-AG is able to induce apoptosis in cytotrophoblasts. On the other hand, morphological studies after acridine orange staining suggest that autophagy may take part in WIN-induced loss of cell viability. All cannabinoids caused a decrease in mitochondrial membrane potential (Δψm) but only 2-AG led to ROS/RNS generation, though no changes in glutathione levels were observed. In addition, ER-stress may be involved in the 2-AG induced-oxidative stress, as preliminary results point to an increase in CCAAT-enhancer-binding protein homologous protein (CHOP) expression. Besides the decrease in cell viability, alterations in cell cycle progression were observed. WIN treatment induced a cell cycle arrest in G0/G1 phase, whereas 2-AG induced a cell cycle arrest in G2/M phase. Here it is reinforced the relevance of cannabinoid signaling in fundamental processes of cell proliferation and cell death in trophoblast cells. Since cannabis-based drugs are the most consumed illicit drugs worldwide and some of the most consumed recreational drugs by pregnant women, this study may contribute to the understanding of the impact of such substances in human reproduction.
Os canabinóides (CBs) podem ser classificados como: fitocanabinóides, os constituintes da planta Cannabis sativa L.; canabinóides sintéticos, sintetizados em laboratório e os endocanabinóides, que são mediadores lipídicos endógenos. Os compostos canabinóides ativam recetores canabinóides – CB1 e CB2. O composto psicoativo mais prevalente é o Δ9-tetrahidrocanabinol (THC), mas mais de 60 diferentes CBs foram já identificados a partir da planta. Os endocanabinóides (eCBs) melhor caracterizados são a anandamida (AEA) e o 2-araquidonoilglicerol (2-AG), que estão envolvidos em vários processos biológicos, incluindo plasticidade sináptica, modulação da dor, homeostasia energética e reprodução. Por outro lado, alguns canabinóides sintéticos, inicialmente projetados para investigação médica, são agora usados como drogas de abuso. Durante o período de desenvolvimento placentário ocorrem processos de remodelação que envolvem proliferação, apoptose, diferenciação e invasão dos trofoblastos. Sabe-se que um controlo rigoroso dos níveis de eCBs é necessário para uma progressão normal da gravidez e que os eCBs estão envolvidos no turnover celular dos trofoblastos. Assim sendo, ao partilharem a ativação dos mesmos recetores, a exposição a exocanabinóides, seja pelo uso recreativo ou medicinal, pode levar a alterações nos níveis de eCBs e na homeostasia do sistema endocanabinóide (ECS). Neste trabalho foi estudado o impacto dos CBs em células trofoblásticas BeWo e em culturas primárias de citotrofoblastos humanos. As células foram tratadas durante 24 horas com diferentes concentrações de THC, do canabinóide sintético WIN-55,212 (WIN) e de 2AG. O tratamento com THC não afetou a viabilidade das células BeWo, enquanto que o WIN e o 2-AG causaram uma perda de viabilidade dependente da dose. Estudos morfológicos, juntamente com marcadores bioquímicos, indicam que o 2-AG é capaz de induzir apoptose em citotrofoblastos. Por outro lado, estudos morfológicos realizados com laranja de acridina sugerem que a autofagia pode estar envolvida na perda de viabilidade induzida pelo WIN. Todos os canabinóides induziram perda de potencial de membrana mitocondrial (Δψm), mas apenas o 2-AG levou a um aumento na formação de ROS/RNS, sem terem sido observadas diferenças nos níveis de glutationa. O stress reticular pode estar envolvido no stress oxidativo induzido pelo 2-AG, visto que resultados preliminares apontam para um aumento na expressão de CCAAT-enhancer-binding protein homologous protein (CHOP). Para além da diminuição da viabilidade celular, os resultados sugerem alterações na progressão do ciclo celular. O tratamento com WIN induziu retenção do ciclo celular em fase G0/G1, enquanto que o 2-AG levou a uma retenção em fase G2/M. Neste trabalho é reforçada a importância da sinalização canabinóide em processos importantes de proliferação e morte celular de células trofoblásticas. Visto que as drogas canabinóides são as mais consumidas a nível mundial, e umas das drogas recreativas mais consumidas pelas mulheres grávidas, este estudo pode contribuir para a compreensão do impacto destas substâncias na reprodução humana.
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Fox, P. J. "Measuring the effects of cannabinoids in multiple sclerosis." Thesis, Exeter and Plymouth Peninsula Medical School, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.700610.
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Ramesh, Divya. "Elevating Endogenous Cannabinoids Reduces Opioid Withdrawal in Mice." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2661.
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Delta9-tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB1 and CB2 cannabinoid receptors, the role these receptors play in reducing opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors, but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this dissertation was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces morphine withdrawal symptoms in in vivo and in vitro models of opiate dependence. Morphine-dependent ICR mice subjected to acute naloxone challenge or abrupt withdrawal (via pellet removal) reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, head shakes, diarrhea, and weight loss. THC and the MAGL inhibitor, JZL184 dose-dependently reduced the intensity of precipitated withdrawal measures through the activation of CB1 receptors. The FAAH inhibitor, PF-3845, reduced the intensity of a subset of precipitated signs through the activation of CB1 receptors, but did not ameliorate the incidence of diarrhea or weight loss. In the next set of experiments, MAGL inhibition dose-dependently reduced the intensity of all spontaneous withdrawal signs (i.e jumps, paw flutters, head shakes, weight loss and diarrhea) in a CB1 receptor dependent manner. However, FAAH inhibition reduced the intensity of head shakes and paw flutters, but did not affect other signs. Strikingly, a combination of low-dose JZL184 and high-dose PF-3845 reduced abrupt withdrawal signs in a manner similar to complete MAGL inhibition, which suggests potential therapeutic advantages of dual enzyme inhibition. This combination elevated appropriate eCB levels and caused moderate CB1 receptor desensitization, but did not affect receptor number in whole brain. Since MAGL, but not FAAH inhibition, blocked diarrhea during opioid withdrawal in vivo, we investigated whether inhibitors of each enzyme would differentially attenuate naloxone-precipitated contractions and secretion in morphine-dependent ilea in vitro. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, and blocked naloxone-precipitated hypersecretion. Thus, these models offer useful tools for investigating in vitro end-ponts of withdrawal, but not for elucidating anti-diarrheal mechanism of these inhibitors.If targeting endocannabinoid catabolic enzymes is indeed a viable approach to treat other abuse disorders, it is important to know whether these inhibitors would themselves have abuse or dependence liability. In the final series of experiments we tested whether prolonged elevation of endocannabinoid leads to the development of cannabinoid dependence, based on the occurrence of somatic withdrawal signs upon challenge with rimonabant, a CB1 receptor antagonist. Repeated treatment with high doses, but not low doses, of JZL184 led to cannabinoid dependnece. These results indicate that the strategy of increasing endogenous cannabinoids through the inhibition of their catabolic enzymes represents a promising approach to ameliorate opioid withdrawal symptoms.
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Nicoll, Gemma Mhairi. "A functional analysis of regulatory regions and polymorphisms surrounding the CNR1 locus." Thesis, University of Aberdeen, 2011. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=186094.
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Changes in the expression of the cannabinoid receptor 1 (CB1) has been associated with the progression of many human diseases such as anxiety and depression, schizophrenia, epilepsy, Huntington’s disease, Parkinson’s disease, obesity and osteoporosis. However, little is known about the mechanisms that control CB1 expression or how they may be affected by human polymorphic variation to bring about disease susceptibility. In order to elucidate the regulatory systems controlling the tissue specific transcriptional regulation of the CNR1 gene, that encodes CB1, and the effects of human polymorphisms on these systems, this study combined comparative genomics, molecular biology, cell biology and pharmacology with human genetics. Comparative genomics was used to identify five evolutionary conserved regions (ECR) 5’ of the CNR1 gene that had been conserved between humans and birds (310 million years). Primary cell culture, using luciferase reporter constructs and transgenic studies suggested that some of these regions acted as enhancers which controlled gene expression in a tissue specific manner. In addition, it was demonstrated that the activity of these ECRs can be altered using different signal transduction agonists. More importantly, evidence is provided to suggest that ECR1 and the endogenous CNR1 promoter work synergistically in primary dorsal root ganglia (DRG) neurons and that ECR2 and the CNR1 promoter work synergistically in primary hypothalamic neurons in response to MAPK and ER agonists. Furthermore, a validated human SNP within ECR1 can interfere with a putative AP-1 transcription factor binding site when the major allele is present to block the up-regulation seen with a MAPK agonist in hippocampal neurons. The discovery of such novel cell specific regulatory pathways and the recognition of the cell specific effects of polymorphisms on these pathways may lead to a better understanding of how CNR1 mis-expression can contribute to disease and will enhance our ability to develop novel therapies.
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Gauson, Lisa. "Novel properties of the phytocannabinoids and their receptors." Thesis, University of Aberdeen, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=109951.
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I have investigated the pharmacological properties of cannabichromene (CBC), cannabigerol (CBG) and Δ8-tetrahydrocannabivarin (Δ8-THCV). A concentrations in the micromolar range, CBG binds to the cannabinoid CB1 and CB2 receptors and acts as a CB1 receptor antagonist. In the functional [35S]GTPγS binding assay performed with mouse brain membranes, CBG also behaves as a potent partial agonist at concentrations less than 100 nM. CBG is an α2-adrenoceptor agonist, and behaves as a competitive 5-HT1A antagonist at concentrations ranging from 300 nM to 10 μM. Further experiments were conducted to explore interactions between established 5-HT1A ligands and the CB1 receptor. In mouse brain membranes, although not in hCB1 transfected cells, the 5-HT1A receptor agonist, 8-OH-DPAT, has the ability both to displace [3H]CP55940 from specific binding sites and to modulate the rate of [3H]CP55940 dissociation from these sites. These results may reflect the presence of CB1-5-HT1A dimers in the brain. Δ9-THCV has been reported to be a potent CB2 receptor antagonist with a KB value lower than its binding affinity for CB2. Experiments were performed in the cAMP assay to establish if Δ8-THCV did in fact target the CB2 receptor. Antagonism of Δ8-THCV was attempted by using a selection of compounds but unfortunately these either behaved as inverse agonists in the assay or as partial agonists. Δ8-THCV induced agonism was Pertussis toxin sensitive. In untransfected CHO cells, Δ8-THCV did not stimulate or inhibit forskolin induced stimulation of cAMP, hence the effects of Δ8-THCV are most likely CB2 dependent. As CBG was found to behave as a potent α2-adrenoceptor agonist and 5-HT1A receptor antagonist, it may be useful clinically, for example for the treatment of depression. Interactions between the 5-HT1A and CB1 receptors need to be explored more fully, not least because it might be possible to exploit such interactions in the clinic.
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Shah, Vibhakar Jayantilal. "Synthesis of cannabidiol stereoisomers and analogs as potential anticonvulsant agents." Diss., The University of Arizona, 1988. http://hdl.handle.net/10150/184523.
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Anticonvulsant activity of cannabidiol (CBD) has been well documented in various laboratory animal species and also in man. As part of our continuing effort to study and to define the structure anticonvulsant relationship several analogs of CBD were synthesized wherein its structural units, namely, the terpene ring, aryl ring and/or side chain were systematically modified. These analogs include the: (1) unnatural (+)-Cannabidol (1b), (2) Delta-3-carenyl analog-(+)-carenadiol (45a), its diacetate (45b) and its 1",1"-dimethylheptyl side chain analog (45c), and (3) unnatural 7-acetoxycannabidiol (46b). (+)-Cannabidiol (1b) was synthesized in about 20-25% yield from olivetol (51) and two different p-menthadienols (67 and 70) as monoterpenoid synthons. (-)-p-Mentha-1,8-dien-3-ol (67) was prepared from (-)-limonene (65) by chromium trioxide-pyridine complex oxidation followed by cerium trichloride assisted sodium borohydride reduction of the obtained ketone (66a). (-)-p-Mentha-2,8-dien-1-ol (70) was synthesized from 1:1 mixture of cis- (69a) and trans-epoxide (68a) of limonene (65) in about 35% yield. The reaction involves phenylselenide anion mediated stereospecific trans-diaxial opening of the epoxide ring to give the required alcohol (70) along with its regioisomer (71) as the major product (79%). The delta-3-carenyl analog (+)-carenadiol (45a) was synthesized from car-4-en-3β-ol (80) and olivetol (51) in about 20% yield. Car-4-en-3β-ol (80) was prepared in about 90-95% yield from the corresponding 3β,4β-epoxy carane (77) by following the same methodology described for (70). The compounds were evaluated for anticonvulsant activity in seizure susceptible (AGS) rats and for neurotoxicity in the rotorod (ROT) test. A general lack of stereoselectivity for the anti-AGS and ROT neurotoxic effects was observed for CBD and its derivatives. Thus (-)-CBD (1a) was marginally more potent than (+)-CBD (1b). But the CBD analog derived from (+)-car-3-ene (72), i.e., (+)-carenadiol (45a), is of interest because of its high protective index (PI = 5.1) and is therefore comparable to(1b) (to which it is stereochemically related) in potency. The 1",1"-dimethylheptyl derivative ((+)-45b), could not separate anticonvulsant activity from neurotoxicity. (Abstract shortened with permission of author.)
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Wheal, Amanda Jane. "Cardiovascular effects of cannabinoids in normotensive and hypertensive rats." Thesis, University of Nottingham, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489969.
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Although cannabinoids cause vasorelaxation of isolated blood vessels, their cardiovascular effects in vivo are complex and may depend on the prevailing experimental conditions or disease states. In this thesis, the regional haemodynamic responses to cannabinoids have been examined in vivo in two rat models of hypertension, in the conscious freelymoving state and under anaesthesia. Parallel in vitro studies were performed in isolated vessels and perfused mesenteric vascular beds. Enhanced vasorelaxation to the endogenous cannabinoid, anandamide, due to an up-regulation of sensory nerve activity, was observed in isolated perfused mesenteric arterial beds from rats chronically treated with L-NAME. In contrast, this enhancement was not seen in isolated mesenteric arterial vessels or in aortic rings, and did not occur in vivo. In conscious rats, the initial bradycardia, renal and mesenteric vasoconstriction, and depressor then pressor responses to anandamide were similar in L-NAME-treated and control rats in vivo, but anandamide caused vasodilatation in the hindquarters vasculature only in control rats. However, in conscious spontaneously hypertensive rats (SHR), but not controls, modest depressor responses to anandamide and the Ii)'nthctic cannabinoid, WIN55212-2, were observed, but were not fully nttrlbutnblc to CHI receptor-mediated vasodilatation. In addition, pressor ro8Jl{J1lIC8 to CBI receptor antagonism occurred only in conscious SHR and WIN hot MIOcioted with vasoconstriction. Furthermore, there was evidence fbr (~UI roceptor-mediated vasoconstriction to anandamide in SHR. Importantly, only in anaesthetised SHR was there evidence for enhanced CBI receptor-mediated vasodilatation, as CHI receptor antagonism caused vasoconstriction and pressor responses. Overall, these in vivo responses suggest a possible up-regulation ofthe endocannabinoid system in SHR, which is most evident under anaesthesia and does not occur in rats made hypertensive by treatment with L-NAME.
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Lu, Tangying (Lily). "Cannabinoids suppress dendritic cell-induced T helper cell polarization." [Tampa, Fla] : University of South Florida, 2006. http://purl.fcla.edu/usf/dc/et/SFE0001790.
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Assareh, Neda. "Studies of cannabinoids in animal models of psychiatric disease." Thesis, University of Nottingham, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.537636.
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Khairy, Hesham A. "Modulation of anandamide actions on the neonatal rat cultured sensory neurone." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=158296.
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The possible role of L-serine as an allosteric modulator of anandamide (AEA) action on cannabinoid receptors has been investigated along with the studying the actions of AEA metabolite, ethanolamine. Dorsal root ganglia (DRG) neurons from neonate Sprague Dawley rats were used in primary culture. L-serine was found to modulate anandamide actions on overall neuronal excitability, voltage-activated K+ and Ca2+ currents and intracellular Ca2+ flux. These modulations were suggested to be mediated via allosteric modulation of AEA actions at CB1 receptors. These observations strengthen previous data obtained from binding studies of L-serine at CB1 receptors. Furthermore, these modulations were abolished by CB1 antagonist, SR141716A, while L-serine alone failed to activate CB1 receptors. We found that L-serine modulations were AEA-dependent and CB1 mediated, while no modulatory effects for L-serine were reported on TRPV1 or GPR55 receptors. Similar modulations were reported from the CB1 allosteric modulator, Org-27569. Ethanolamine was fond to enhance the intracellular Ca2+ level via influencing thapsigargicin- and caffeine-sensitive calcium stores. Ethanolamine actions were not abolished in PTX-treated DRG neurones or in the presence of CB1 antagonist, SR141716A indicating that these actions were conducted independently from CB1 receptors and inhibitory G-proteins. Additionally, ethanolamine modulated the voltage- activated potassium currents independently from its effect on intracellular Ca2+ level. In conclusion CB1 receptor modulation by ligands acting at an allosteric site may provide a novel approach to endocannabinoids-mediated therapies.
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Tanner, Carolyn. "Novel pharmacology of putative cannabinoid targets and their ligands." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=158821.
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The novel compound VSN16R was characterised and its functional effect in the central nervous system and periphery was investigated. VSN16R behaved as an agonist in the mouse isolated vas deferens assay. The functional effect of VSN16R appeared to involve GPR55 and GPR18 activation. The possibility that in addition to the CB1 receptor; the CB2 receptor, GPR55 and GPR18 contribute towards the effects of certain cannabinoid ligands in the nervous system (both central and peripheral) was investigated. Results suggest that the cannabinoid CB2 receptor and also GPR55 and GPR18 are functional in the mouse vas deferens. The results imply that in addition to the CB1 receptor, the CB2 receptor can mediate the effects of certain cannabinoids, including CP55940, AEA and Δ9-THC, but not JWH015 in the [35S]GTPγS assay with brain region membranes. GPR55 can mediate the effects of certain cannabinoids, including CP55940 and JWH015 in the [35S]GTPγS assay with brain region membranes. GPR55 was also shown to mediate the effect of JWH015, but not O-1602 in the mouse isolated vas deferens assay, indicating an additional target for O-1602 in this tissue. Data obtained suggest that CP55940 and AEA, but not Δ9-THC, O-1602 or JWH015 can activate GPR18. The effect of cannabinoid ligands and VSN16R on human neutrophil migration was investigated. The functional effect of a range of phytocannabinoids and the ligand N-arachichidonoyl glycine (NAGly) at the receptor GPR902 was investigated. The findings implied that CBD, CBG and Δ9-THC acid may be able to interact with GPR92 to antagonise the GPR92 agonist lysophosphatidic acid.
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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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Creasy, Blaine Madison. "Inflammatory regulation of cysteine cathepsins /." Unavailable until 8/19/2013, 2008. http://hdl.handle.net/10156/2273.
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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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Gilliam, Bruce Lawrence 1962. "APPROACHES TO THE SYNTHESIS OF SIMPLIFIED ANALOGS OF CANNABIDIOL." Thesis, The University of Arizona, 1986. http://hdl.handle.net/10150/276559.
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Scollo, Mimmo. "The antimitogenic effect of the cannabinoid receptor agonist WIN 55212-2 on human melanoma cells is mediated by the membrane lipid raft." Thesis, Universita' degli Studi di Catania, 2011. http://hdl.handle.net/10761/312.
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Melanoma is characterized by a poor prognosis. Therapeutic strategies for melanoma alternative to surgery are still under investigation, as all current treatments for this tumor appear scarcely efficient. In the light of these data, new strategies are required for the treatment of this disease. Cannabinoids have been shown to possess proapoptotic properties on different tumor cell types, and for this reason considered candidate molecules for innovative treatment of melanoma. In this work, the effects of the non selective cannabinoid receptors agonist WIN 55,212-2, have been studied on different human melanoma cell lines expressing CB1 and CB2 cannabinoid receptors. Interestingly, WIN induced a significant increase of cell death rate in melanoma cell cultures. Such effect did not appear mediated by either CB1or CB2 receptors. In fact, both the selective CB1 antagonist AM-251 and the selective CB2 antagonist AM-630, alone or in combination, were not able to protect melanoma cell lines by WIN-induced apoptosis. Similarly, both ACEA, a selective CB1 agonist and JWH-133, a selective CB2-R agonist, were not able to induce apoptosis in melanoma cells. Cannabinoids also interact with the Vanilloid Receptor 1(VR1) which is also expressed by various melanoma cell lines. However, SB366791, a potent, selective VR1 competitive antagonist, was not able to prevent WIN-induced apoptosis. Recently, other mechanisms have been hypothesized to explain WIN-55,212-dependent cell death, such as, for example, the pathway related to the membrane lipidic raft. In fact, methyl-à à ²-cyclodextrin, a membrane cholesterol depletor, partially prevented WIN-induced cell death associated with activation of caspases with the involvement of both the extrinsic and intrinsic apoptosis pathways. From the bulk of data, it appears plausible to hypothesize that along with multiple mechanisms underlying cannibinoid-mediated apoptosis, the pathways related with the lipid rafts are significantly involved in cannabinoid dependent melanomatous cell death. Finally, the lipid raft system could represent a novel molecular target for innovative treatment of melanoma.
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Agudelo, Marisela. "Cannabinoids Induce Immunoglobulin Class Switching to IgE in B Lymphocytes." [Tampa, Fla] : University of South Florida, 2009. http://purl.fcla.edu/usf/dc/et/SFE0003014.
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Puighermanal, Puigvert Emma 1983. "Molecular mechanisms underlying the effects of cannabinoids in the brain." Doctoral thesis, Universitat Pompeu Fabra, 2011. http://hdl.handle.net/10803/53574.
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The endocannabinoid system is an endogenous neuromodulatory system that regulates a plethora of physiological functions, including the control of movement, memory, anxiety, and pain, among others. Cannabinoid compounds are mainly found in the Cannabis sativa plant and exert their effects by acting at the endocannabinoid system. Cannabinoids are potential therapeutic agents, mainly for multiple sclerosis, pain, and emesis, although an important caveat to their use is the possible adverse effects, such as memory impairment and anxiety. This thesis mainly addresses the molecular mechanisms underlying some of the physiological processes controlled by the endocannabinoid system as well as specific pharmacological effects triggered by 9-tetrahydrocannabinol, the main psychoactive compound of marijuana plant. The combination of biochemical, pharmacological, and behavioral approaches allowed the elucidation of certain signaling cascades responsible for particular effects induced by cannabinoids.El sistema endocannabinoid és un sistema neuromodulador endogen que regula diverses funcions fisiològiques, incloent el control del moviment, la memòria, l’ansietat i el dolor, entre altres. Els compostos cannabinoids es troben principalment a la planta Cannabis sativa i exerceixen els seus efectes actuant al sistema endocannabinoid. Els cannabinoids tenen potencial terapèutic, principalment per l’esclerosi múltiple, el dolor i l’èmesi, tot i que una limitació important pel seu ús recau en els possibles efectes adversos, tal com l’alteració de la memòria i l’ansietat. Aquesta tesi exposa principalment els mecanismes moleculars responsables d’alguns processos fisiològics controlats pel sistema endocannabinoid així com efectes farmacològics desencadenats pel 9-tetrahidrocannabinol, el principal compost psicoactiu de la planta de marihuana. La combinació d’aproximacions bioquímiques, farmacològiques i comportamentals ha permès revelar algunes cascades de senyalització responsables de determinats efectes induïts pels cannabinoids.
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Grey, Jonathan Andrew. "The effects of cannabinoids on the ingestive behaviour of mice." Thesis, University of Birmingham, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.650806.
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