Abstract
Cancer is inherently linked to pain, making it one of the most common symptoms in cancer patients during the progression, and even remission, of the disease. Specifically, cancer-induced bone pain (CIBP), one of the most frequent forms of cancer pain associated with skeletal metastases, is poorly managed by current analgesic treatments and has become a major area of unmet medical need. To understand the mechanisms underpinning CIBP, the studies presented herein were designed to examine, at both the molecular and circuit level, manifestations of pain in rodent models of CIBP during both disease progression (rat and mouse) and regression (rat).The results evidence how, following cancer cell tibial implantation, CIBP female rats developed progressive mechanical and thermal heat hypersensitivity in behavioural assays concurrent to progressive trabecular and cortical bone degeneration. While this behavioural phenotype did not correlate with alterations in the electrophysiological properties of spinal deep dorsal horn neurons, diffuse noxious inhibitory controls (DNIC), a unique form of descending modulation, were found to be dysfunctional one week following cancer cell implantation but recovered on posterior weeks. Targeted diphtheria toxin cancer cell ablation on week one led to 1) prolonged DNIC dysregulation, 2) stabilisation of pain-like behaviours, and 3) reversal of bone degeneration. These results were followed by the establishment of a female and male mouse tibial CIBP model, which faithfully recreated the mechanical hypersensitivity and progressive trabecular and cortical bone degeneration observed in the rat CIBP model, with a mirrored impact on DNIC expression. Wishing to tie central nervous system manifestations of pain (dysfunctional DNIC) to activity in the peripheral nervous system, primary afferent activity was measured in naïve mice at the level of the dorsal root ganglion, demonstrating that DNIC evocation had no impact on mass activity. These findings not only expand our understanding of the neural basis of the complex mechanisms driving CIBP, highlighting the dynamic nature of the disease and the need for tailored and mechanistically targeted therapeutical approaches, but also lay the foundation for future studies that will interrogate the synergy between central and peripheral nervous system manifestations of pain.
| Date of Award | 1 Jun 2024 |
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| Original language | English |
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| Supervisor | Kirsty Bannister (Supervisor), Stephen McMahon (Supervisor), Franziska Denk (Supervisor) & Ryan Patel (Supervisor) |