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Title: Intracellular mechanisms in chronic pain states
Author: Delaney, Ada
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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Neuropathic pain is a pervasive chronic condition that lacks adequate therapeutic treatment, making the identification of new candidate targets for drug development a priority. Underlying the development of this pathological pain state is a process of neuronal plasticity, termed central sensitisation that results in hyperexcitability of sensory neurons in the spinal cord. Stimulation of peripheral nociceptive inputs can cause downstream activation of kinases in the spinal dorsal horn that may contribute to the generation of this hyperexcitable state in the spinal cord. Here, using the chronic constriction injury (CCI) model of neuropathic pain, the role played by p42/44 and p38 mitogen-activated protein (MAP) kinases was addressed. Inhibition of both the p42/44 and p38 MAP kinase pathways attenuated the behavioural reflex sensitisation seen following nerve injury. The study explored the part played by spinal VPAC2 and NK2 receptors, (which respond to the afferent excitatory neuropeptides VIP and NKA respectively), in addition to glially mediated events in the activation of these kinases. Following nerve injury, both spinal activation of p42/44 and p38 MAP kinases and behavioural sensitisation (which was sensitive to p42/44 and p38 pathway inhibitors) was prevented by VPAC2, NK2 and NMDA receptor antagonists and glial or TNF-a inhibitors. The NMDA receptor, which is thought to be crucially involved in central sensitisation in the spinal cord, binds to the multivalent adapter protein PSD-95; an interaction which is necessary for the development of neuropathic behavioural reflex sensitisation. Here we show that mutant mice expressing a single point mutation in the Src homology 3 (SH3) domain of PSD-95 (PSD-95SH3W470L mutants), have intact neuropathic behavioural reflexes but blunted inflammatory responses. These findings indicate that different domains of the same protein may contribute selectively to different pain states. Examining further the role played by PSD-95, we found that the expression of both PSD- 95 and one of its signalling partner kinases, Pyk 2, was increased in the same superficial dorsal horn neurons following nerve injury. These studies suggest the importance of specific receptors and signalling pathways, non-neuronal cells and of protein:protein complexes associated with the NMDA receptor in chronic pain states and point to their future potential in the design of novel therapeutic targets.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available