Wong, Y.M.; (2007) Investigation of the central molecular events that maintain persistent inflammatory pain states. Doctoral thesis , University of London.

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Abstract

Noxious stimulation of the periphery leads to long-term changes in the excitability of dorsal horn neurons of the spinal cord. In the spinal cord the increased excitability of dorsal horn neurons requires the activation of a subset of superficial dorsal horn projection neurons that express the NK1 receptor. These lamina I neurons are crucial for the initiation and maintenance of persistent pain states and are the origin of a spino-bulbo-spinal loop that drives descending spinal facilitation, in part, via serotonergic axons. In many areas of the central nervous system some aspects of synaptic plasticity are thought to be controlled by the immediate early gene and transcription factor zif268 (also known as Egr-1, Krox-24 and NGF1-A). In the hippocampus, for example, zif268 is necessary for both late-LTP (long-term potentiation) and learning and memory. In the spinal cord, the expression of zif268 is activity dependant and associated with the induction of LTP in the dorsal horn. Here, I have shown that peripheral inflammation of the hindpaw with Complete Freund's Adjuvant (CFA) increased zif268 expression in dorsal horn neurons and was necessary for the development and maintenance of the inflammatory pain state. In addition, descending serotonergic pathways and lamina I projection neurons modulate spinal c-fos and zif268 expression following peripheral inflammation. Depletion of spinal serotonin increased c-fos expression without affecting zif268 expression in the dorsal horn following peripheral inflammation. However, in contrast, the ablation of lamina I NK1 expressing neurons in the dorsal horn that project to the brainstem significantly decreased spinal zif268 expression. The glucocorticoid receptor (GR) and serum- and glucocorticoid inducible kinase 1 (SGK1) are involved in synaptic plasticity and are potential downstream targets of zif268. I investigated the behavioural role of spinal GR following peripheral inflammation and the consequence of altering zif268 levels on GR and SGK1 expression in the dorsal horn. Using an antisense approach I show that both SGK1 and GR expression are regulated by zif268. I also demonstrated that GR expression in the dorsal horn was crucial for the maintenance of inflammatory pain states. While GR expression was positively regulated, SGK1 was negatively regulated by zif268 during the early stages of peripheral inflammation. In conclusion, these results indicate that zif268 dependent gene regulation in the dorsal horn is pivotal to the maintenance of inflammatory pain states and offer potential new targets for the development of future analgesic drugs.

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