UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

An Investigation into Noxious Mechanosensation, and the Role of Peripheral Neuron Subpopulations in Pain

Fuller, Alice Morgan; (2021) An Investigation into Noxious Mechanosensation, and the Role of Peripheral Neuron Subpopulations in Pain. Doctoral thesis (Ph.D), UCL (University College London).

[thumbnail of Alice M Fuller PhD Thesis With Corrections.pdf] Text
Alice M Fuller PhD Thesis With Corrections.pdf
Access restricted to UCL open access staff until 1 April 2022.

Download (4MB)

Abstract

This thesis uses transgenic mice to explore the role of candidate and known mechanotransducers in acute mechanical pain. It also utilises transgenics to ablate whole populations of sensory neurons in mice to establish what role these also have in pain, both under normal and inflammatory conditions. The water and ion channel Aquaporin 1 (Aqp1) is preferentially expressed in the small diameter neurons of the peripheral nervous system (PNS). These are responsible for nociception, and Aqp1 has previously been implicated in pain sensation. Its role in acute mechanical pain has not fully been explored. By using global Aqp1 knockout (Aqp1KO) mice and mechano-clamp electrophysiology I am the first to demonstrate that Aqp1 contributes to the mechanically activated (MA) currents associated with pain sensing in nociceptors. However, it does not produce MA currents when expressed in naïve cells. Aqp1 is necessary for normal mechanical pain in vivo as Aqp1KO animals have an increased mechanical pain threshold. Thus, it is unlikely that Aqp1 is a pore-forming component of a noxious mechanotransducer but may form part of a membrane complex essential to mechanical pain sensation. Piezo2 is a known mammalian mechanotransducer and is responsible for light touch sensation and proprioception. It’s contribution to mechanical pain under pathological conditions is established but it’s role in acute mechanical pain remains controversial. I generate mice with a nociceptor-specific Piezo2 deletion and again use a combination of electrophysiological and behavioural assays to demonstrate that Piezo2 is not required for acute noxious mechanosensation. Thus, my data confirms that the mechanotransducer responsible for mechanical pain remains ambiguous. Finally I study the role of the cutaneous population of Parvalbumin-positive (PV+) sensory neurons in pain. This population is required for innocuous mechanical sensation including vibration sensing. By genetically ablating PV+ neurons to generate ‘PVDTA’ mice, I provide evidence that these neurons are necessary for negatively regulating the thermal, mechanical, and inflammatory pain response, as behaving animals are hypersensitive to these insults. I am the first to propose that cutaneous PV+ neurons are responsible for closing the so-called ‘pain gate’ in the dorsal horn of the spinal cord. Further evidence for this comes from an in vivo electrophysiological study of dorsal horn neurons in PVDTA mice, which exhibit increased excitability as a consequence of noxious stimulation. In vivo DRG neuron imaging in animals expressing a reporter protein in PV+ sensory neurons show that these neurons are capable of responding to noxious stimuli, thus solidifying this hypothesis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: An Investigation into Noxious Mechanosensation, and the Role of Peripheral Neuron Subpopulations in Pain
Event: University College London
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
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
URI: https://discovery.ucl.ac.uk/id/eprint/10123446
Downloads since deposit
3Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item