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Peripheral Mechanisms of Touch and Pain

Sexton, JE; (2016) Peripheral Mechanisms of Touch and Pain. Doctoral thesis , UCL (University College London). Green open access

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Abstract

This thesis uses transgenic approaches to alter expression of candidate mechanosensors in physiological and pathological conditions to determine their contribution to the sensations of touch and pain. Transient receptor potential (TRP) ion channels have highly conserved roles in sensory function and a great deal of evidence implicates them in the process of mechanotransduction. Their propensity to form heteromeric complexes as well as the functional redundancy they exhibit makes them difficult to study. We used animals with global deletion of multiple canonical TRP (TRPC) channels to minimise the effects of these features and found that TRPC1, TRPC3, TRPC5 and TRPC6 have a modality specific and combinatorial role in innocuous mechanosensation. Next, we looked at the role of TRPC channels and TRPA1 and TRPV1 in mechanical hypersensitivity in the monosodium-iodoacetate (MIA) model of Osteoarthritis (OA). The results show TRPC3, TRPC6 and TRPV1 do not contribute to mechanical hypersensitivity in OA. However, TRPA1 appears to be necessary for the full manifestation of OA induced mechanical hypersensitivity. We also investigated the role of Annexin A6 in mechanosensation and OA. The Annexin A6 protein binds to NMB-1, a blocker of mechanically activated currents. We found that it negatively regulates mechanosensation and that by overexpressing the protein using a gene therapy approach we are able to partially attenuate mechanical hypersensitivity in the MIA model of OA. Finally, we investigated the role of ASIC4 in pain and mechanosensation through generation and behavioural characterisation of a global knockout mouse. The function of ASIC4 is largely unknown but in vitro it regulates expression and function of other ASIC subunits, some of which have roles in noxious and mechanosensory processes. We found a role for ASIC4 in formalin induced pain and in visceral inflammation which is the first report of a somatosensory function for this poorly understood protein.

Type: Thesis (Doctoral)
Title: Peripheral Mechanisms of Touch and Pain
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: https://discovery.ucl.ac.uk/id/eprint/1475391
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