Breast cancer has the highest incidence rate in women, accounting for more than 22% of all cancers and possessing a strong disposition to metastasize to bone. These skeletal metastases become a significant cause of morbidity and mortality in patients with the primary symptom being pain. Pain is a major concern in determining a patient’s quality of life and there have been many attempts to understand and control bone pain with little success. Previous studies have shown that glutamate plays a role in bone cancer pain, with an excess in free glutamate able to cause pain either directly through excitotoxic pathways or indirectly though the dysregulation of osteoclasts and osteoblasts, causing bone dysregulation. TRPV-1 receptors have also has been implicated in the mechanisms of bone cancer pain, as osteoclasts release protons during bone remodeling which can elicit a TRPV-1-related nociceptive response from neurons in the surrounding periosteum. Capsazepine was identified during a high throughput screen of 30,000 compounds to be a potent inhibitor of breast cancer cell-mediated glutamate release, a neurotransmitter with known associations in neural signaling, bone homeostasis, and pain. Capsazepine also has antagonistic effects on transient receptor potential vanilloid type 1 (TRPV-1) receptors which act as key players in both heat and vanilloid-induced nociception. These findings suggest that Capsazepine may provide a multi-site effect for the treatment of cancer-induced bone pain. An animal model of breast cancer-induced bone pain involved intrafemorally injecting MDA-MB-231 cancer cells to measure pain. Behavioural tests are then performed measuring dynamic weight bearing and paw withdrawal thresholds. These measurements are used to demonstrate both movement-evoked and spontaneous pain-related behaviour of the affected limb. Using Capsazepine, we demonstrate a dose-dependent attenuation of pain behaviour in vivo, while confirming tumour presence using immunohistochemistry (IHC). We show that TRPV-1 and glutamate play an important role in the onset and severity of bone cancer pain and blocking these pain pathways provide relief from pain commonly associated with cancer in the bone. / Thesis / Master of Health Sciences (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/15970 |
| Date | 11 1900 |
| Creators | Balenko, Matthew |
| Contributors | Singh, Gurmit, Health Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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