Show simple item record

dc.contributor.authorWallace, Victoria C. J.en
dc.date.accessioned2018-01-31T11:39:38Z
dc.date.available2018-01-31T11:39:38Z
dc.date.issued2003en
dc.identifier.urihttp://hdl.handle.net/1842/27605
dc.description.abstracten
dc.description.abstractChronic neuropathic pain, characterised by allodynia (perception of innocuous stimuli as painful) and hyperalgesia (facilitated responses to painftil stimuli), is poorly understood and is usually resistant to classical analgesics. Such abnormal pain phenomena can be associated with human demyelinating conditions such as Charcot-Marie-Tooth disease. Using mouse models of peripheral nerve demyelination, we have provided evidence for the consequent establishment of neuropathic pain and investigated possible underlying mechanisms. The first model investigated was the Prx-mi\\ mouse. The murine periaxin gene (Prx) is expressed in Schwann cells and encodes L- and S-periaxin, two abundant PDZ-domain proteins thought to have a role in stabilisation of myelin in the peripheral nervous system (PNS). Prx-null mice show progressive demyelination in peripheral nerves and electrophysiological investigations indicate the presence of spontaneous action potential discharge; abnormal activity thought to be critical for the development of persistent pain states. Consistent with the time course of demyelination, Rrx-null mice display an increased behavioural reflex sensitivity to cutaneous mechanical and noxious thermal stimulation. To further investigate the link between demyelination of peripheral nerves and neuropathic pain, we have also characterised a novel model of focal peripheral nerve demyelinating neuropathy. Focal demyelination of the sciatic or saphenous nerve was induced with lysolecithin (lysophosphatidylcholine) and resulted in an increased behavioural reflex sensitivity to both thermal and mechanical tests, peaking at 9-14 days following treatment. Nerve morphology was investigated using light and electron microscopy, which revealed 30- 40% demyelination of the treated nerve, (without lysolecithin-treated axon loss) coinciding with peak behavioural changes. Changes in the excitability of saphenous nerves were revealed, with spontaneous action potential discharge of 2-3 impulses per second present at peak behavioural change. No associated change in peripheral activation thresholds or conduction velocity was observeden
dc.description.abstractIn both models, immunohistochemical investigations revealed no cell loss in the dorsal root ganglia (DRG) and no evidence for axonal damage. Similar methods revealed changes in the expression of neuropeptide Y, and the sodium channels Nav1.3 and Nav1.8 in DRG neurones. Such changes may account for increased nerve excitability and are known to occur in other models of nerve injury. However, these changes in the demyelinating models occur in a more restricted manner, specifically in the cells of formerly myelinated fibres. Intrathecal injections of the selective NMDA receptor antagonist, [R]-CPP, indicated that NMDA receptor-dependent changes are crucial for the development of a neuropathic pain like state following peripheral nerve demyelination. Intrathecal administration of pharmacological agents indicated a role for the transcription factor NFkB in the production of the behavioural reflex sensitivity of lysolecithin-treated mice, as well as identifying the endogenous cannabinoid system as an effective inhibitory regulator and potential analgesic target.en
dc.description.abstractThis study describes the first mouse models of peripheral nerve demyelination designed for the study of neuropathic pain and reveals phenotypic changes in DRG, which may contribute to the development of a neuropathic pain-like state. Therefore, these models may be useful for the evaluation of novel therapeutic targets for the treatment of demyelination-associated neuropathic pain.en
dc.publisherThe University of Edinburghen
dc.relation.isreferencedbyen
dc.subjectAnnexe Thesis Digitisation Project 2017 Block 16en
dc.titlePeripheral nerve demyelination and neuropathic painen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelen
dc.type.qualificationnamePhD Doctor of Philosophyen


Files in this item

This item appears in the following Collection(s)

Show simple item record