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|Autori: ||Bolognini, Daniele|
|Tutor interno: ||PAROLARO, DANIELA|
|Co-tutore: ||PERTWEE, ROGER|
|Titolo: ||Pharmacological properties of the phytocannabinoids Δ9-tetrahydrocannabivarin and cannabidiol.|
|Abstract: ||Cannabis and its derivatives have been used for medicinal purpose for thousand of years. More recently, the main cannabis constituents, cannabinoids, have been found to act and target at cannabinoid as well as other receptors. This brought particular interest around the pharmacology of phytocannabinoids and their possible clinical applications. The research object of this study focused on two phytocannabinoids, Δ9-tetrahydrocannabivarin (Δ9-THCV) and cannabidiol (CBD), and it has been divided in three individual investigations:
In the first study, we investigated the pharmacology of Δ9-THCV at cannabinoid type 1 (CB1) and type 2 (CB2) receptors. We found and confirmed that Δ9-THCV acts as antagonist at CB1 receptors in experiments of [35S]GTPγS binding assay on human CB1-CHO (Chinese hamster ovary) cell membranes. Also, in the same set of experiments, Δ9-THCV displayed a slight inverse agonism at CB1 receptors, which was confirmed in experiments of cyclic AMP assay in hCB1-CHO cells. At CB2 receptors, we found that Δ9-THCV can behave as a partial agonist when the measured response is inhibition of forskolin-induced stimulation of cyclic AMP production in hCB2-CHO cells or stimulation of [35S]GTPγS binding to membranes obtained either from hCB2-CHO cells or from mouse spleen membranes. No such effect was displayed by Δ9-THCV in untransfected CHO cells, pertussis toxin (PTX)-treated hCB2-CHO cells or CB2 -/- mouse spleen membranes.
In collaboration with Dr. Barbara Costa and Dr. Dino Maione, we also showed that Δ9-THCV shares the ability of established selective CB2 receptor agonist to reduce signs of inflammation and inflammatory pain (Guindon, Hohmann 2008). These experiments were performed on in vivo models of λ-carrageenan-induced oedema and thermal hyperalgesia, and formalin-induced nociception.
In the second investigation we brought further evidences that Δ9-THCV is a partial agonist at CB2 receptors. In detail, we applied a protocol to hCB2-CHO cells in order to convert the selective CB2 receptor antagonist/inverse agonist, AM630, into an apparent neutral antagonist. In these experimental conditions, we found that Δ9-THCV still behaves as a CB2 receptor agonist and is antagonized by AM630 in experiments of cyclic AMP assay. Additional tests were also conducted to better understand the pharmacology of the ligand, AM630, at CB2 receptors.
In the third study, we investigated the effect of CBD at serotonin type 1A (5-HT1A) autoreceptors. This research was based on previous in vivo findings showing that CBD-induced anti-emetic and anti-nausea effects were mediated by somatodendritic 5-HT1A autoreceptors located in the raphe nuclei (Rock et al. 2009, Parker et al. 2010). Experiments of [35S]GTPγS binding conducted in rat brainstem membranes revealed that CBD, in a bell-shaped manner, is able to enhance the dose-response curve of the selective 5-HT1A receptor agonist, DPAT. In addition, our results suggest that CBD does not interact directly with 5-HT1A receptors, and that CBD-mediated DPAT dose-response curve enhancement might implicate the involvement of an other receptor.|
|Parole chiave: ||phytocannabinoids, inflammation, Δ9-tetrahydrocannabivarin, cannabidiol, 5HT1A receptors|
|MIUR : ||BIO/14 FARMACOLOGIA|
|Corso di dottorato: ||Neurobiologia|
|Ciclo di dottorato: ||23|
|Università di conseguimento titolo: ||Università degli Studi dell'Insubria|
|Citazione: ||Bolognini, D.Pharmacological properties of the phytocannabinoids Δ9-tetrahydrocannabivarin and cannabidiol. (Doctoral Thesis, Università degli Studi dell'Insubria, 2010).|
|Phd_thesis_bolognini_completa.pdf||testo completo tesi||1,22 MB||Adobe PDF||Visualizza/apri
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