Munns, Clare Hannah; (2008) Mechanisms and plasticity of cold sensitivity in peripheral neurons. Doctoral thesis , UCL (University College London).

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Abstract

The aim of this thesis was to characterise the molecular mechanisms involved in cold transduction in peripheral neurons. Members of the transient receptor potential (TRP) family of cation channels are currently recognised as the principal transducers of thermal stimuli in sensory neurons, and two channels, TRPM8 and TRPA1, have been implicated in cold sensation. Ratiometric calcium imaging and quantitative rt-PCR studies revealed that cold sensitivity in sympathetic neurons and in a significant proportion of sensory neurons is independent of TRPM8 and TRPA1 expression, suggesting the presence of a further cold-sensitive ion channel in these cells. Previous studies had suggested that voltage-gated potassium channels may also be important in the regulation of cold transduction. In calcium imaging experiments, pharmacological blockade of potassium channels unmasked a novel cold sensitivity in previously unresponsive populations of sensory and sympathetic neurons. Moreover, the individual potassium channels underlying these effects differ between neuronal populations, as demonstrated by the differing effects of specific potassium channel blockers on sensory and sympathetic neurons. The chemotherapeutic drug oxaliplatin induces an acute cold hypersensitivity in patients, and has been suggested to act on voltage-gated sodium channels. The activation of sodium channels alone did not alter cold sensitivity in sensory neurons, however the application of oxaliplatin to dissociated cells induced a qualitative change in the cold response, with neurons displaying a unique bursting response pattern. Cold-sensitive neurons are dependent on NGF during development, and a further aim of the thesis was to investigate the influence of this growth factor on cold sensitivity in neonatal sensory neurons. NGF induced an up-regulation of cold sensitivity and functional TRP channel expression. In the case of TRPM8, this effect was mediated via the Runx1 transcription factor, which is known to be expressed in NGF-dependent neurons during development.

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