Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.733166
Title: Emerging targets for analgesics to control inflammatory pain
Author: Torres Perez, Jose Vicente
ISNI:       0000 0004 6496 4095
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Abstract:
Burn injury is followed by one of the most severe inflammatory conditions and associated with one of the most excruciating persistent pain. Current therapeutics for burn injury-associated pain are limited and produce undesired side effects. The development and particularly the maintenance of persistent pain depend on plastic changes in neurons involved in the processing of noxious stimulation-evoked (nociceptive) information including nociceptive primary sensory neurons and spinal dorsal horn neurons. Those plastic changes include changes in gene expression that are regulated largely by epigenetic mechanisms including post-translational modification of histones. Here, I show inflammatory conditions including that following burn injury significantly and specifically up-regulates, both in a group of primary sensory neurons and spinal dorsal horn neurons, the expression of phosphorylated serine 10 in histone H3 (pS10H3), a transcriptionally permissive histone mark. This up-regulation is associated, in superficial spinal cord neurons, with up-regulation in the expression of cFos a known marker for nociceptive processing. In superficial spinal cord neurons, these up-regulations depend on the activation of the N-methyl-D aspartate receptor, extracellular signal-regulated kinase 1 and 2 and mitogen and stress-activated kinase 1 and 2 (MSK1/2). Importantly, deletion of MSK1/2 blocks the development of inflammatory heat hyperalgesia. Further, blocking the voltage-gated sodium channel type 1.7 significantly reduces pS10H3 up-regulation both in primary sensory neurons and superficial spinal dorsal horn neurons. I conclude that pS10H3 represents a novel marker for nociceptive processing both in primary sensory and superficial spinal dorsal horn neurons, and transcriptional changes downstream of S10H3 phosphorylation are pivotal in the development of inflammatory heat hyperalgesia. I further conclude that Nav1.7 is a promising target for the control of heat hyperalgesia in burn injury.
Supervisor: Nagy, Istvan ; Bantel, Carsten Sponsor: Chelsea & Westminster Healthcare
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.733166  DOI:
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