Genetic approaches to somatosensation.
Doctoral thesis, UCL (University College London).
Three approaches to understanding peripheral pain pathways are described in this thesis. Cre-loxP technology has been used to delete genes specifically in specialised sensory neurons that respond to tissue damage (nociceptors). The sodium channel selective Nav1.8 promoter is used to drive Cre expression. I used a mouse expressing diphtheria toxin A-chain downstream of a floxed stop signal, crossed with the Nav1.8Cre mouse to delete all cells expressing this channel. This lead to massive cell loss of nociceptive neurons, associated with altered pain behaviour. The mice lost cold, mechanical and inflammatory pain, but not thermal or neuropathic pain behaviour. These observations are consistent with modality specific pain pathways in the peripheral nervous system. Microarray analysis was used to identify the transcripts selectively expressed in the lost sensory neurons, providing potential new analgesic drug targets for inflammatory pain. In a further study exploiting knock out mice, I identified a line that had lost sensitivity to light touch, but was otherwise normal in terms of pain pathways. This sensory loss was due to the insertion of a LacZ cassette in a gene encoding Papin a PDZ-protein of unknown function. Further analysis showed a loss of interactions between sensory neurons and mechanosensitive Merkel cells, and a loss of sensory neuron numbers. Finally, conditional deletion of Nav1.7 in mice, and global loss of Nav1.7 in man have been shown to lead to a loss of pain sensitivity. I used a recently discovered peptide blocker of Nav1.7 to examine the role of this channel in normal mice. I found that Nav1.7 block leads to a loss of mechanical, inflammatory and neuropathic pain, making this sodium channel a very attractive analgesic drug target.
|Title:||Genetic approaches to somatosensation|
|Additional information:||Permission for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Genetics, Evolution and Environment|
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