Pain
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Bone cancer pain can be difficult to control, as it appears to be driven simultaneously by inflammatory, neuropathic and tumorigenic mechanisms. As nerve growth factor (NGF) has been shown to modulate inflammatory and neuropathic pain states, we focused on a novel NGF sequestering antibody and demonstrated that two administrations of this therapy in a mouse model of bone cancer pain produces a profound reduction in both ongoing and movement-evoked bone cancer pain-related behaviors that was greater than that achieved with acute administration of 10 or 30 mg/kg of morphine. This therapy also reduced several neurochemical changes associated with peripheral and central sensitization in the dorsal root ganglion and spinal cord, whereas the therapy did not influence disease progression or markers of sensory or sympathetic innervation in the skin or bone. Mechanistically, the great majority of sensory fibers that innervate the bone are CGRP/TrkA expressing fibers, and if the sensitization and activation of these fibers is blocked by anti-NGF therapy there would not be another population of nociceptors, such as the non-peptidergic IB4/RET-IR nerve fibers, to take their place in signaling nociceptive events.
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Pain sensitivity reflects a balance between pain facilitatory and inhibitory systems. To characterize the relationships between these systems we examined the interactions between the analgesic effects of morphine and the anti-analgesic effects of the pro-inflammatory cytokine interleukin-1 (IL-1). We report that administration of a neutral dose of IL-1beta abolished morphine analgesia in mice, whereas acute or chronic blockade of IL-1 signaling by various IL-1 blockers (IL-1 receptor antagonist (IL-1ra), alpha-melanocyte-stimulating hormone, or IL-1 tri-peptide antagonist) significantly prolonged and potentiated morphine analgesia. ⋯ Indeed, genetic or pharmacological blockade of IL-1 signaling prevented the development of tolerance following repeated morphine administration. Moreover, acute administration of IL-1ra in wild type mice, either immediately following the cessation of acute morphine analgesia, or following the development of chronic morphine tolerance, re-instated the analgesia, suggesting that blockade of the IL-1 system unmasks the analgesic effect of morphine. These findings suggest that morphine produces an IL-1-mediated homeostatic response, which serves to limit the duration and extent of morphine analgesia and which underlies the development of tolerance.
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Clinical Trial Controlled Clinical Trial
Hypersensitivity to cutaneous thermal nociceptive stimuli in irritable bowel syndrome.
Irritable bowel syndrome (IBS) is a common intestinal ailment of which the pathophysiological mechanisms are not well understood. Most IBS patients demonstrate enhanced perception, visceral hypersensitivity, in response to distension of the gut lumen but there are conflicting results about changes in somatic sensitivity. This study focused on the possible contribution of abnormal pain sensitization due to positive feedback (vicious pain cycle) that affects somatic tissues due to viscero-somatic convergence. ⋯ Sensitization of IBS patients was not limited to symptomatic dermatomes (calf) but extended evenly across the body, including to the face (no sensitization gradient from foot to face). Also, the difference between IBS and control groups did not depend on the evoked pain intensity level, i.e. the degree of sensitization of IBS patients was similar near threshold (10% on the visual analog scale) and at higher intensities. Lastly, no correlation was found between IBS subjects' pain sensitivity of any of the three test sites and their ratings of spontaneous pain.