Sharkey, Keith A.Van Sickle, Marja2017-12-182017-12-182006http://hdl.handle.net/1880/102054Bibliography: p. 157-186Some pages are in colour.Cannabinoids inhibit nausea and vomiting (emesis), but their mechanism is unknown. The aim of the following studies was to determine if cannabinoids are part of an endogenous cannabinoid system involved in inhibiting emesis in the brainstem. An anatomical substrate for the anti-emetic effect was demonstrated by the presence of the cannabinoid receptor 1 (CB1r) in the nucleus of the solitary tract and the dorsal motor nucleus of the vagus in the brainstem by immunohistochemistry and Western blotting. CB1r was also found in the myenteric plexus of the stomach and duodenum. A role for the CB1r in the modulation of emesis was revealed by observing a reduction in the number of episodes of retching and vomiting in ferrets that had been administered an emetic stimulus and a CB1r agonist and showing that the action of cannabinoids was reversed by a selective CB1r antagonist. A low dose of the cannabinoid delta-9- tetrahydrocannabinol inhibited emesis when applied directly to the brainstem demonstrating a central site of action. Fos immunohistochemistry was used to show that cannabinoids reduce emesis-induced neuronal activation in the area postrema, nucleus of the solitary tract and dorsal motor nucleus of the vagus nerve. The presence of endocannabinoids was demonstrated by evaluating the anti-emetic potential of endocannabinoids and determining their levels in the brainstem during an emetic response. The enzymes that degrade endogenous cannabinoids were also found in the brainstem by immunohistochemistry. A relationship between endocannabinoids and other neurotransmitter systems involved in emesis was suggested by the comparison of the immunoreactivity of CB1 r with substance P, the NK1 receptor and serotonin. Another cannabinoid receptor, CB2r, was shown to be present and functional and involved in the anti­emetic effect of cannabinoids. The involvement of the endocannabinoid system in emesis and the establishment of the site of action in the dorsal vagal complex of the brainstem provides new avenues for further study of the targeting of pharmaceuticals and future research into the cellular mechanism of cannabinoids in the brain.xiii, 187 leaves : ill. ; 30 cm.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.doctoral thesis10.11575/PRISM/1053