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Cancer pain is exceedingly common and has tremendous impact on quality of life. In spite of this, mechanisms underlying such pain are not well understood. It is estimated that almost 30% of all patients with cancer pain do not obtain relief from currently available therapies; fully 50% of cancer patients suffer from pain despite treatment.
(Illustrations courtesy of Dr. Patrick Mantyh)
Cancers can often metastasize to bone. Over 70% of patients with breast or prostate carcinoma show skeletal metastases, which are present in >90% of people who die from breast or prostate carcinomas. Prostate cancer is the second most common malignancy in men over age 55. Our goal is to understand the mechanisms of cancer pain, especially bone cancer pain. We implant cancer cells into the femur of mice and follow the growth of the tumor, the resorption of the bone and changes that occur in the sensory nervous system. The latter reveals the â€œmolecular signatureâ€� of bone cancer pain that arises from the growth and biological features of the tumor and the changes in bone density produced by human cancer cells. The goal of these studies is to identify innovative strategies for therapeutic intervention to limit pain either directly, or as a consequence of inhibiting tumor proliferation. Therapies can also include approaches to build bone preventing fracture and enhancing quality of life.
Pain is normally produced by high-intensity stimuli which either produce damage to tissues or which have the potential to do so. This evolutionary adaptation increases our chances of survival by avoiding tissue damage. Neuropathic pain results from injuries to nerves and represents an abnormal pain state because it is produced by stimuli that do not cause injuries (e.g., light touch). The anomalous interpretation of a normally innocuous stimulus as pain by the nervous system reflects tremendous plasticity following injury to nerves, such as by trauma (including surgery), cancer chemotherapy, diseases including diabetes or viral eruptions (e.g., herpes zoster or shingles).
Common neuropathic pain states include diabetic neuropathy, trigeminal neuralgia, post-herpetic neuralgia. The pain is debilitating and resistant to treatment. Our goal is to understand the neural adaptations upon nerve injury, including the expression of new transmitters (such as NPY) and proteins (such as sodium channels) in sensory neurons that did not previously express these substances and their relationship to this pathological pain state.
The figures show NPY immuno-reactivity progressing from the cell body (on the right) towards the site of the injury and the lack of co-localization of NPY (red) with markers of small diameter cells, including substance P, CGRP (shown; green) and IB4 in the dorsal root ganglia. The new expression of NPY in large diameter sensory neurons becomes an integral part of the touch pathway after nerve injury. Blockade of transmission at synapses in the touch pathway may be a novel strategy to suppress chronic neuropathic pain. Eventually, the goal is to understand why the brain now interprets touch as pain.
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