Journal
NEUROSCIENCE LETTERS
Volume 463, Issue 1, Pages 49-53Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2009.07.051
Keywords
Ceramide; Nitroxidative stress; Neuronal apoptosis; Peroxynitrite; Morphine tolerance
Categories
Funding
- AHA Fellowship
- [1 R01 DA024074-01A1]
- [1 R21 DA023056-01A2]
- [R01 HL077328]
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Opiates, like morphine, are the most effective analgesics for treating acute and chronic severe pain, but their use is limited by the development of analgesic tolerance and hypersensitivity to innocuous and noxious stimuli. Because opioids are a mainstay of pain management, restoring their efficacy has great clinical importance. We have recently demonstrated that spinal ceramide, a sphingolipid signaling molecule plays a central role in the development of morphine antinociceptive tolerance. We now report that ceramide upregulation in dorsal horn tissues in response to chronic morphine administration is associated with significant neuronal apoptosis. Inhibition of ceramide biosynthesis attenuated both the increase in neuronal apoptosis and the development of antinociceptive tolerance. These findings indicate that spinal ceramide upregulation is a key pro-apoptotic event that occurs upstream of the development of morphine antinociceptive tolerance and support the rationale for development of inhibitors of ceramide biosynthesis as adjuncts to opiates for the management of chronic pain. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
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