Kucharczyk, Mateusz Wojciech; (2019) Cancer-induced Bone Pain: Peripheral and Central Mechanisms in Rodent Models of the Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cancer pain remains a major area of unmet medical need. One common form of chronic cancer pain, affecting 400,000 people each year in the US alone, is associated with skeletal metastases. These pains are typically mechanoceptive in nature and poorly managed by available analgesics. Here, I employed in vivo imaging using GCaMP6s to assess the properties of the nerve fibres that transduce bone cancer pains. I showed that a subclass of nociceptors, those that are normally mechanically insensitive, are recruited and activated in a rodent model of bone cancer, and that this dramatically increases sensory input from the diseased tissue to the central nervous system. The recruitment of these so-called silent afferents was shown to be Piezo2-dependent. Next, utilising in vivo spinal electrophysiology, I showed that the increased peripheral input described above leads to the reorganization of descending noradrenergic controls, potently increasing inhibitory tone. I hypothesise the existence of a spino-pontine-spinal loop that modulates spinal excitability in a noradrenergic fashion and is strongly altered in the advanced metastatic disease. This changes the spinal pharmacology of a2–adrenoceptor antagonist atipamezole, which now has inhibitory actions at the level of the spinal cord. Diffuse Noxious Inhibitory Controls (DNIC), a unique form of descending noradrenergic controls, was studied also. This phenomenon, whereby application of a noxious stimulus to one part of the body inhibits pain perceived in a remote body region, acts through inhibitory descending pathways. Interestingly, DNIC were found dynamic with the progression of bone tumours. I hypothesise that DNIC originate from brain regions separate to those that govern tonic NA-controls, and I conclude that the expression status of DNIC can be used clinically as a diagnostic tool to tailor pain pharmacotherapy in patients suffering from chronic bone cancer pain. The unique properties of bone silent afferents, which show plasticity in chronicity, combined with ensuing central events offer several novel opportunities for targeting metastatic bone pain. Due to the dynamic nature of the disease and resulting pains, it is crucial to match pain therapy with the stage of the disease.

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