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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Neuronal plasticity in the pain-processing pathway is thought to be a mechanism underlying pain hypersensitivity and negative emotions occurring during a pain state. Recent evidence suggests that the activation of astrocytes in the anterior cingulate cortex (ACC) contributes to the development of negative emotions during pain hypersensitivity after peripheral inflammation. However, it is unknown whether these activated astrocytes contribute to neuronal plasticity in the ACC. ⋯ The long-term facilitation in the CFA-injected mice was inhibited by the astroglial toxin, the N-methyl-d-aspartate (NMDA) receptor antagonist and NMDA receptor glycine binding site antagonist. The increase of intracellular Ca(2+) concentration in astrocytes during HFS was higher in the CFA-injected mice than in the control mice and was inhibited by l-α-aminoadipate (l-α-AA). These results suggest that the activation of astrocytes in the ACC plays a crucial role in the development of negative emotions and LTP during pain hypersensitivity after peripheral inflammation.
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Opioid therapy offers the promise of reducing the burden of chronic pain in not just individual patients, but among the broad population of patients with chronic pain. Randomized trials have demonstrated that opioid therapy for up to 12-16weeks is superior to placebo, but have not addressed longer-term use. In the United States, opioid sales have quadrupled during 2000-2010, with parallel increases in opioid accidental overdose deaths and substance abuse admissions. ⋯ Long-term opioid therapy appears to be associated with iatrogenic harm to the patients who receive the prescriptions and to the general population. The United States has, in effect, conducted an experiment of population-wide treatment of chronic pain with long-term opioid therapy. The population-wide benefits have been hard to demonstrate, but the harms are now well demonstrated.
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Hundreds of genes are proposed to contribute to nociception and pain perception. Historically, most studies of pain-related genes have examined them in isolation or alongside a handful of other genes. More recently the use of systems biology techniques has enabled us to study genes in the context of the biological pathways and networks in which they operate. ⋯ The Web site can be used to find out more about a gene of interest by looking at the function of its interaction partners. It can also be used to interpret the results of a functional genomics experiment by revealing putative novel pain-related genes that have similar expression patterns to known pain-related genes and by ranking genes according to their network connections with known pain genes. We expect this resource to grow over time and become a valuable asset to the pain community.