Abstract
Chronic pain presents a global challenge, with its pervasive impact on individualsaccumulating to have significant socioeconomic consequences worldwide. Despite
this, there is a distinct lack of effective therapies largely due to a limited understanding of the biological mechanisms that lead to and sustain chronic pain.
This thesis takes a human-first approach to investigating mechanisms of pain,
comprised of three core studies:
1: A Genetic study of nociception in healthy participants: A novel adaptive recall by
genotype was used to study common variants in the candidate gene TRPA1 on pain
sensation. Interim results suggested a subtle effect of rs7819749 on heat pain threshold, though this was not sustained in the final analysis. Simulations confirmed the validity of the adaptive design.
2: A Population-Scale Genetic Analysis of Chronic Pain in the UK Biobank: This study
explores the impact of control cohorts on genetic associations, and the advantages of
using no-chronic-pain control cohort comparator. It then uses this control cohort to
investigate non-synonymous variation across chronic pain associated conditions
revealing putative and novel pain gene candidates. This approach differs from previous genetic studies of pain, which carefully define cases but often neglect control group selection, particularly in automated analyses which have revealed few genetic
associations with chronic pain to date.
3. The development of methods to study generator potentials in human nociceptors via microneurography: Using the electrical threshold tracking of the nociceptor I
demonstrate reduction in electrical threshold during sub-noxious heating. In addition, I provide pilot data of the effects of the TRPV1 agonist capsaicin, and the local anaesthetic lidocaine on the generator potential.
Together, these studies establish a framework from population-scale genetic discovery to mechanistic hypothesis testing in humans, ultimately supporting the development of novel medicines for the treatment and prevention of chronic pain.
| Date of Award | 9 Dec 2025 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Anthony Edward Pickering (Supervisor) & Jim Dunham (Supervisor) |