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Title: Role of 5-hydroxytryptamine (5-HT) in urinary bladder signalling and colon-bladder cross-organ sensitization
Author: Konthapakdee, Nipaporn
ISNI:       0000 0004 6349 0895
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2017
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This thesis investigates the role of 5-HT in bladder sensory (afferent) signalling in healthy animals and in a mouse model of colon-bladder cross-sensitization. We primarily address the effect of 5-HT and involvement of different 5-HT receptor subtypes on afferent nerve activity using in vitro extracellular nerve recordings. 5-HT is known to be a key neurotransmitter that regulates many essential roles in the body including the bowel but less is known about 5-HT's role in the urinary bladder. Moreover, research has focused on the role of 5-HT on bladder efferent nerves and muscle contraction, while the role of 5-HT on bladder afferent nerves is still an enigma. We have investigated 5-HT receptor expression in the urothelium and determined the effect of 5-HT on urothelial signaling and its contribution to bladder afferent activity, examining both mechanosensitive and spontaneous nerve firing. In addition, the role of 5-HT on bladder afferent activity was investigated in a TNBS-induced colonic inflammation model of colon-bladder cross-sensitization. Finally we examined whether the urinary bladder has an endogenous source of 5-HT. We have made a number of novel findings: (i) various 5-HT receptors transcripts were expressed in mouse urothelium with a notable exception of 5-HT3 receptors. Cultured urothelial cells examined using calcium imaging responsed directly to 5-HT demonstrating that these 5-HT receptors are functional; (ii) 5-HT exerted excitatory effect on spontaneous afferent firing but attenuated mechanosensitive responses to distension, these actions were mainly mediated through 5-HT3 receptors, and were independent from muscle contraction; (iii) the effects of 5-HT on spontaneous and mechanosensitive firing were attenuated in the post-inflammatory state of colonic TNBS-treated mice. There was an accompanying downregulation in SERT mRNA expression in the urothelium; (iv) citalopram, a selective 5-HT reuptake inhibitor, attenuated mechanosensitive afferent discharge which was reversed by the 5-HT3 antagonist, granisetron. mRNA expression of 5-HT producing enzymes, TPH1 and TPH2, and SERT were detected in the urothelium. 5-HT positive cells were expressed in mouse urethra but not in the bladder dome. We conclude that 5-HT has the potential to modulate bladder afferent signaling by direct actions on the afferent nerves and indirect effects via the urothelium with nitric oxide playing a modulatory influence. The urothelium contains the necessary molecular machinery for endogenous 5-HT production but the extent to which this 5-HT contributes to bladder signaling in normal and diseased states requires further investigation and may represent a novel therapeutic target to treat bladder symptoms.
Supervisor: Grundy, David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available