The descending noradrenergic system forms part of the body's endogenous analgesic system, however there are conflicting views as to the exact role the system plays during the development of the neuropathic pain phenotype. The experiments described in this thesis aim to explore the longitudinal changes in descending noradrenergic control following nerve injury and the potential utility of selective noradrenaline re-uptake inhibitors in the treatment of neuropathic pain. All experiments were performed on adult male Wistar rats using a combination of behavioural, immunohistochemical and electromyographical techniques. Using a method chronic intrathecal catheterisation, it was found that administration of an uz adrenoceptor (AR) antagonist at day 3 following nerve injury revealed the early onset of allodynia and hyperalgesia. However, as the phenotype progressed, uz-AR antagonism had no effect over allodynia however could still modulate heat hyperalgesia. There was also a reduced noradrenergic innervation to the lumbar dorsal horn in nerve injured rats. Combined, this suggested a progressive failure of the noradrenergic system to prevent the onset of ipsilateral behavioural hypersensitivity. Interestingly, uz-AR antagonism also unmasked contralateral allodynia and hyperalgesia and was associated with an increase in lumbar dorsal horn c-fos expression. Changes in the descending noradrenergic modulation of bilateral heat hypersensitivity mediated by AD- versus C-heat nociceptors was then explored in anaesthetised rats. These experiments further suggested a functional deficit in noradrenergic control, opposed to uz -AR desensitisation, which contributes to the onset of neuropathic ipsilateral hypersensitivity. Further investigations involved pharmacologically restoring descending noradrenergic tone and observing the effects on the development of the neuropathic pain phenotype. It was shown that chronic intrathecal dosing with reboxetine (a selective noradrenaline re-uptake inhibitor) from the time of nerve injury could suppress the onset of allodynia. In addition, the effects of intrathecal versus systemic administration of reboxetine for alleviating spontaneous and evoked neuropathic pain behaviours were also examined, alongside a discussion of the potential clinical implications.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:682352 |
| Date | January 2014 |
| Creators | Hughes, Sam |
| Publisher | University of Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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