The endocannabinoid system (ECS) has been identified in the urinary bladder of humans and rats and is purported to play a modulatory role in detrusor overactivity (DO). Clinical studies demonstrated that cannabis improves urgency in patients with neurogenic DO. However, how endocannabinoids are regulated in vivo as well as the pathophysiological relevance of deregulation of the system in the aetiopathogenesis of DO remain unexplored. This thesis explores the clinical relevance of the ECS in the aetiopathogenesis of DO, by evaluating the effects of cannabinoid agonists on bladder contractions in vitro and in vivo. Cannabinoid receptor (CBR) expression was localised in human and rat bladders. In vitro, ACEA (CB1 agonist) had both pre- and postsynaptic effects on bladder contraction, while GP1a (CB2 agonist) only had postsynaptic effect. CB1 receptor was co-localised with ChAT (choline acetyltransferase enzyme) in human detrusor but not in the urothelium, while CB2 co-localised with ChAT in both urothelium and detrusor. qRT-PCR showed that CB1 receptor was significantly upregulated by 2.8-fold in the urothelium of DO patients and downregulated by 3.2-fold in the detrusor of DO patients compared to normal. Rat cystometry experiments demonstrated CP55,940 (CBR non-selective agonist) significantly increased micturition interval (MI) and bladder capacity (BC) by 52±5.5% and induced a 25 ± 2.9% decrease in maximal pressure (MP). Addition of CP55,940 to rats with induced bladder irritation, showed an increase in MI by 78% ± 16.7% and a 22% ± 5.8% reduction in MP. In conclusion, cannabinoid receptors are involved in normal micturition at both peripheral and CNS sites, data supported by in vitro studies where CB1 reduced neuronal activity and where both cannabinoid receptors modulated bladder contractility. CB1 receptors expressed in afferent fibre endings in the urothelium could influence bladder function. CB1 receptor agonists may be useful for future treatment of DO as there is altered CB1 receptor expression in these bladders.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:666659 |
| Date | January 2015 |
| Creators | Bakali, Evangelia |
| Contributors | Tincello, Douglas; Lambert, David |
| Publisher | University of Leicester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2381/33068 |
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