Date of Award

Spring 5-15-2013

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Interstitial cystitis or painful bladder syndrome (IC/PBS) is a chronic pain syndrome affecting 3-6% of women in the US. Some evidence suggests urothelial injury may cause some cases of IC/PBS. To examine how urothelial injury modulates bladder pain, three injury models were used: Infection with uropathogenic Escherichia coli (UPEC, inflammatory), Protamine sulfate (PS, non-inflammatory chemical), and lipopolysaccharide (LPS, non-infectious and inflammatory) treatment. Surprisingly, injury with PS decreased, while UPEC alone increased the pain response to bladder distention. These data suggest that changes in the urothelium may modulate some forms of IC/PBS. However, in most cases, patients with IC/PBS have no histological abnormalities. Therefore, other molecular mediators may modulate IC/PBS.

Glutamate, the major excitatory neurotransmitter in the CNS, modulates a host of physiological responses through the actions of ionotropic (iGluRs) and metabotropic receptors (mGluRs). Metabotropic glutamate receptor 5 (mGluR5) has previously been shown to have an important role in somatic inflammatory and neuropathic pain models. However, there is limited evidence that mGluR5 in the CNS has a role in bladder pain. To determine the function of mGluR5 in non-inflammatory bladder pain, mice with a targeted genetic deletion of mGluR5 (mGluR5 KO) were used. Both mGluR5 KO mice and mice given a specific mGluR5 antagonist (fenobam) had a reduced bladder pain response. Systemic treatment with fenobam in mice infected with UPEC also resulted in a reduced response to bladder distention. Thus suggesting that mGluR5 is necessary for the full expression of inflammatory and non-inflammatory bladder pain.

However, these techniques do not indicate the site of action because mGluR5 is expressed throughout the pain neuroaxis. Antagonism of mGuR5 in the right central nucleus of the amygdala (CeA) is analgesic in a somatic inflammatory injury model. To examine the role of mGluR5 in the CeA, pharmacological activation of Group I mGluRs (mGluR5 and 1) was examined. Activation of mGluR5/1 in the CeA was sufficient to increase the pain response to noxious bladder distention. Additionally, pharmacological inhibition and virally mediated conditional deletion of mGluR5 in the CeA reduced the evoked response to bladder distention. Finally, optogenetic activation of the CeA increases the pain response to bladder distention suggesting that mGluR5 activation increases neuronal excitability in the CeA, increasing sensitivity to bladder distention. Overall, these data suggest a role of urothelial injury and mGluR5 in bladder pain.

Language

English (en)

Chair and Committee

Robert W Gereau

Committee Members

Yu-Qing Cao, Michael C Crowder, Scott J Hultgren Indira U Mysorekar

Comments

Permanent URL: https://doi.org/10.7936/K7PZ56RB

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