Chronic pain is a debilitating condition that affects approximately 20% of adults, yet effective treatments remain sparse. This is partly due to an inadequate representation of clinical pain in animal models utilised during drug development. The UVB and heat re kindling (UVB/HR) model is a promising model of chronic inflammatory pain, however the presence of central sensitisation is contentious. The first part of this project utilised centrally acting, MK-801, in electromyographic (EMG) recordings to objectively validate the induction of central sensitisation in the rat UVB/HR model, providing an essential step toward future utility in pre-c1inical trials. The UVB/HR model was utilised in subsequent studies as a model of inflammatory pain. It is well documented that nociception can be modulated supraspinally, with previous studies suggesting a differing contribution from the cerebellum, depending on the cerebellar lobe activated. However, these studies involved either visceral (rather than somatic) nociception or electrical activation, where confounds such as current spread are important limitations. Previous studies also did not consider the modular organization of the cerebellum . In terminally anaesthetized rats, chemical activation (with DLH) of the cerebellar cortex of module A in the posterior and anterior lobe produced a pronociceptive effect. This was demonstrated by a decrease in EMG threshold to mechanical stimulation. Activation of lateral vermal lobule VIII also produced robust pronociception in naive rats but had no effect in UVB/HR rats. This is possibly due to other supraspinal sites playing a more central role in pain states and masking effects from the cerebellum. EMG recordings involve a polysynaptic withdrawal reflex pathway and thus the site of spinal nociceptive modulation following cerebellar cortical activation was unclear. To try and address this issue the effect of cerebellar stimulation on monosynaptic H reflex amplitude was examined. No detectable effect was found, suggesting the changes in EMG withdrawal responses were unlikely due to alteration in motor neurons alone. Finally, extracellular recordings from spinal dorsal horn neurons were obtained to determine whether cerebellar activation alters processing of noxious sensory inputs. Results from this part of the study were inconclusive, potentially due to the heterogeneity of the cell population, where it is possible that descending control from the cerebellum targets a particular subset of neurons in the dorsal horn that were not recorded in our study. Overall the novel findings reported in this thesis suggest that various modules of the cerebellum can be pharmacologically manipulated to alter nociceptive reflex responses in naive animals, but may have a lesser effect in lasting pain states.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:687602 |
| Date | January 2014 |
| Creators | Weerasinghe, Nirosha S. |
| Publisher | University of Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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