Stress-induced visceral pain in rodents: neurochemical, hormonal, immune and epigenetic mechanisms

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dc.check.date10000-01-01
dc.check.embargoformatNot applicableen
dc.check.infoIndefinite
dc.check.opt-outYesen
dc.check.reasonNo embargo requireden
dc.check.typeNo Embargo Required
dc.contributor.advisorCryan, John F.en
dc.contributor.advisorDinan, Timothy G.en
dc.contributor.authorMoloney, Rachel D.
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2015-06-02T15:38:40Z
dc.date.available2015-06-02T15:38:40Z
dc.date.issued2014
dc.date.submitted2014
dc.description.abstractVisceral pain is a debilitating disorder which affects up to 25% of the population at any one time. It is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. Currently the treatment strategies are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. The work presented in this thesis aimed to redress this issue and look in more detail at the molecular mechanisms of visceral pain in preclinical models. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here a mouse model of early-life stress-induced visceral hypersensitivity was validated. Moreover, mouse strain differences were also apparent in visceral sensitivity suggesting a possible genetic component to the underlying pathophysiology. Furthermore, gender and sex hormones were also implicated in stress sensitivity and visceral pain. Using the rat model of maternal separation, some of the epigenetic mechanisms underpinning visceral hypersensitivity, specifically the contribution of histone acetylation were unravelled. Glutamate has been well established in somatic pain processing, however, its contribution to visceral pain has not been extensively characterised. It was found that glutamate uptake is impaired in viscerally hypersensitive animals, an effect which could be reversed by treatment with riluzole, a glutamate uptake activator. Moreover, negative modulation of the metabotropic glutamate (mGlu) receptor 7 was sufficient to reverse visceral hypersensitivity in a stress sensitive rat strain, the Wistar Kyoto rat. Furthermore, toll-like receptor 4 (TLR4) was implicated in chronic stress-induced visceral hypersensitivity. Taken together, these findings have furthered our knowledge of the pathophysiology of visceral pain. In addition, we have identified glutamate transporters, mGlu7 receptor, histone acetylation and TLR4 as novel targets, amenable to pharmacological manipulation for the specific treatment of visceral pain.en
dc.description.sponsorshipScience Foundation Ireland (07/CE/B1368 and 12/RC/2273)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMoloney, R. 2014. Stress-induced visceral pain in rodents: neurochemical, hormonal, immune and epigenetic mechanisms. PhD Thesis, University College Cork.en
dc.identifier.urihttps://hdl.handle.net/10468/1836
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2014, Rachel Moloney.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectStressen
dc.subjectRodent modelsen
dc.subjectGlutamateen
dc.subjectEpigeneticen
dc.subjectGender differences in pain sensitivityen
dc.subjectVisceral painen
dc.thesis.opt-outtrue
dc.titleStress-induced visceral pain in rodents: neurochemical, hormonal, immune and epigenetic mechanismsen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Medicine and Health)en
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