Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.647220
Title: An investigation into the epigenetic regulation of nociceptive processing
Author: Tochiki, K. K.
ISNI:       0000 0004 5365 8324
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Abstract:
The induction of pain states is known to involve changes in gene expression in DRGs and spinal dorsal horn. These changes lead to plasticity in both peripheral and central pathways in the form of peripheral and central sensitisation, which contribute to the full manifestation of pain states. Strong evidence exists to implicate the regulation of pain states by epigenetic mechanisms. Histone modification contributes to long-term plasticity and modulation of gene expression and histone modifying enzymes have been shown to regulate memory formation, a process thought to require neural activity similar to central sensitisation. Specifically, both neural processes engage the same molecular events such as extracellular signal-regulated kinase (ERK) activity, which induces the histone modification phosphorylation of histone H3 at serine 10 (PH3S10) via the nuclear mitogen and stress-activated protein kinase (MSK1). MSK1 has been implicated in various animal models of neural plasticity and PH3S10 is a known marker of transcriptional activation, but neither has been investigated following noxious stimulation. The aim of this thesis was to use the rat formalin model, which induces a biphasic nocifensive behavioural response reflective of peripheral nociceptor activation followed by central sensitisation maintained by ongoing peripheral input, to investigate the role of histone modifications, in particular PH3S10, in pain processing. This thesis demonstrated using immunohistochemistry that hindpaw formalin stimulation caused induction of PMSK1 and PH3S10 in the ipsilateral dorsal horn. PH3S10 peaked at 30 minutes and colocalised with markers of the pain pathways PERK, NK1, c-Fos, and Zif268. Formalin-induced PMSK1 and PH3S10 were prevented by inhibition of upstream ERK activity with the MEK inhibitor SL327. Moreover, intrathecal delivery of the MSK1 inhibitor SB747651A prevented full expression of PH3S10, and attenuated both phases of the formalin response. These findings are the first to elucidate key players involved in ERK/MAPK regulation of pain processing, and suggest that histone phosphorylation plays a crucial role in the response to injury.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.647220  DOI: Not available
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