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dc.contributor.advisorTorsney, Carole
dc.contributor.advisorBrunton, Paula
dc.contributor.advisorColvin, Lesley
dc.contributor.authorWilson, Kirsten
dc.date.accessioned2022-04-27T14:02:31Z
dc.date.available2022-04-27T14:02:31Z
dc.date.issued2022-04-27
dc.identifier.urihttps://hdl.handle.net/1842/38903
dc.identifier.urihttp://dx.doi.org/10.7488/era/2157
dc.description.abstractChronic pain is a significant clinical burden and available treatments are inadequate. Progress has been made in understanding and targeting underlying pain mechanisms but to target pain efficiently, we must understand why some patients are more vulnerable to developing chronic pain than others. This thesis examines the influence of environmental and genetic factors on pain sensitivity and chronic pain development. Chemotherapy-induced neuropathic pain (CIPN) is a common and debilitating side effect of chemotherapy treatment. However not all patients develop CIPN, and for those that do, severity varies. Cancer patients often undergo surgery prior to chemotherapy. A prior adult injury has been implicated in chronic pain vulnerability; however, a prior surgical insult has never been investigated in relation to CIPN vulnerability and was explored here. Hindpaw surgical incision did not significantly alter the development of CIPN in the oxaliplatin rat model. Rats develop dynamic allodynia at the incision site, which peaked on post-surgical day two and recovered by day seven. This was accompanied by a change in skin structure. Immunohistochemical investigation revealed the development of putative dermal papillae within 24 hours, with papillae numbers peaking on post-surgical day two. Ordinarily, dermal papillae house Meissner’s corpuscles, specialised nerve endings responsible for sensing dynamic touch which are implicated in dynamic mechanical allodynia. Markers for Meissner’s corpuscles reveal their development at the incision site, within the dermal papillae, peaking at post-surgical day 3, and disappearing by post-surgical day 7; with this time course matching that of post-surgical dynamic allodynia. This phenomenon occurs in both sexes. Furthermore, Brain Derived Neurotrophic Factor (BDNF), that is vital for Meissner’s corpuscle development, was increased at the incision site at the peak of the phenomenon. Altered sensitivity has been observed in neurodevelopmental disorders but not explored in epilepsy aphasia syndrome, where a rare heterozygous mutation of the GRIN2A gene, encoding the GluN2A NMDA receptor subunit, has been identified. Here a novel Grin2A rat model was used to investigate genetic impact on sensitivity and inflammatory pain development. Sensitivity was not altered in the heterozygous Grin2A-/+ model of epilepsy aphasia syndrome; however, Grin2A-/- animals exhibited mechanical hyposensitivity while thermal and cold sensitivity were unaffected. Genotype had no effect on (Complete Freunds’ Adjuvant) CFA-induced hypersensitivity. Results suggest no alteration in sensitivity in epilepsy aphasia syndrome but highlight the importance of GluN2A in mechanical sensitivity. Subsequent anatomical investigations in Grin2A-/- animals revealed no significant alterations in skin innervation, cell bodies or central termination pattern of primary afferents. This thesis highlights a potentially novel mechanism contributing to dynamic allodynia, with the development of Meissner’s corpuscles at the incision site amplifying input during central sensitisation. In addition, this work highlights the importance of GluN2A in mechanical sensitivity circuits.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.titleImpact of environmental and genetic factors on pain sensitivity and chronic pain developmenten
dc.title.alternativeThe impact of environmental and genetic factors on pain sensitivity and chronic pain developmenten
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2027-04-27en
dcterms.accessRightsRestricted Accessen


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