Pain
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Common cancers, including cancers of the breast, lung, and prostate, frequently metastasize to multiple bones where they can cause significant and life-altering pain. Similar to cancer itself, the factors that drive bone cancer pain evolve and change with disease progression. Once cancer cells have metastasized to bone, both the cancer cells and their associated stromal cells generate pain by releasing algogenic substances including protons, bradykinin, endothelins, prostaglandins, proteases, and tyrosine kinase activators. ⋯ Tumor growth in bone can also generate a neuropathic pain by directly injuring nerve fibers as well as inducing an active and highly pathological sprouting of both sensory and sympathetic nerve fibers that normally innervate the bone. This structural reorganization of sensory and sympathetic nerve fibers in the bone, combined with the cellular and neurochemical reorganization that occurs in the spinal cord and brain, appears to contribute to the peripheral and central sensitization that is common in advanced bone cancer pain. These mechanistic insights have begun to lead to advances in both how we understand and treat bone cancer pain.
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Recent research suggests that exercise can be effective in reducing pain in animals and humans with neuropathic pain. To investigate mechanisms in which exercise may improve hyperalgesia associated with prediabetes, C57Bl/6 mice were fed either standard chow or a high-fat diet for 12 weeks and were provided access to running wheels (exercised) or without access (sedentary). The high-fat diet induced a number of prediabetic symptoms, including increased weight, blood glucose, and insulin levels. ⋯ These results confirm that elevated hypersensitivity and associated neuropathic changes can be induced by a high-fat diet and exercise may alleviate these neuropathic symptoms. These findings suggest that exercise intervention could significantly improve aspects of neuropathy and pain associated with obesity and diabetes. Additionally, this work could potentially help clinicians determine those patients who will develop painful versus insensate neuropathy using intraepidermal nerve fiber quantification.
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Treating bone cancer pain poses a major clinical challenge, and the mechanisms underlying bone cancer pain remain elusive. EphrinB-EphB receptor signaling may contribute to bone cancer pain through N-methyl-d-aspartate receptor neuronal mechanisms. Here, we report that ephrinB-EphB signaling may also act through a Toll-like receptor 4 (TLR4)-glial cell mechanism in the spinal cord. ⋯ Intrathecal administration of an exogenous EphB1 receptor activator, ephrinB2-Fc, increased the expression of TLR4 and the levels of IL-1β and TNF-α, activated astrocytes and microglial cells, and induced thermal hypersensitivity. These ephrinB2-Fc-induced alterations were suppressed by spinal knockdown of TLR4. This study suggests that TLR4 may be a potential target for preventing or reversing bone cancer pain and other similar painful processes mediated by ephrinB-EphB receptor signaling.