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Title: Peripheral and central mechanisms in chronic human inflammatory and neuropathic pain and associated animal models
Author: Durrenberger, Pascal F.
ISNI:       0000 0004 2737 4862
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2007
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The neuro-inflammatory mechanisms in chronic neuropathic pain are poorly understood, particularly in the central nervous system (CNS), and represent important targets for the development of novel analgesics. Inflammation associated with nerve injury produces a number of pathogenic chemical mediators of which prostanoids are a potent component. Recent studies show that inflammatory processes may contribute to neuropathic pain. Cyclooxygenases (Cox-1 and Cox-2) are the enzymes responsible for prostanoid production. Cyclooxygenase-2 (Cox-2) sensitise sensory neurones via the EP1 receptor. We have investigated EP1 and EP4 receptors, Cox-1 and Cox-2 expression and glial activation in human nerves, dorsal root ganglia (ORG) and in the chronic constriction injury (CCI) rat model, using immuno-histological and autoradiographic methods. T cell mediated immune response (Cathepsin S and lymphocytes) were investigated in human injured peripheral nerves. EP1 and Cox-2 were also investigated in the human CNS. Since plasticity and neuro-degenerative processes are thought to play an important role in generating chronic pain, particularly de-afferentation pain, inhibitory mechanisms on axonal regeneration (Nogo and its receptor) were also investigated. Human and rodent tissues were immunostained with antibodies to EP1, EP4, Cox-1, Cox-2, cathepsin S, CDS and CD4 (lymphocyte markers), Nogo-A and Nogo-66 receptor (myelin associated protein and receptor), prior to image analysis. To assess macrophage/microglial cells, antibodies to CD68 (human macrophage marker), OX-42 (rat microglial marker), ferritin (microglia/macrophage-IIke cell marker) or radioligand PK11195 (marker of glial activation) were used. In human nerves, Cox-1 and Cox-2 immunoreactivity was detected in cells with morphology and distribution similar to microglia/macrophage-IIke cells. EP1 and Cox-2 expression was significantly Increased in human nerve proximal to injury. While there was a rapid Increase in EP1-fibres and CD68 positive macrophages, Cox-2 increase was apparent later reaching a peak at 4 - 6 weeks after injury, but was persistent in human painful neuromas for years. Cox-1 expressing cells appeared after the transient Cox-2 peak and remained present over many years. Sensory neurones in injured human DRG showed a significant acute increase of EP1-IR intensity. EP4-IR was found to be increased in injured peripheral nerves (acute, chronic and neuromas) while decreased in injured DRG sensory neurones (acute and chronic) suggesting a translocation of the protein from the soma on to the proximal nerve axon after injury. Cathepsin S levels were increased immediately after injury and lasted only for a period of 2 weeks with the gradual appearance of lymphocytes thereafter.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available