TY - JOUR
T1 - Spinal ceramide and neuronal apoptosis in morphine antinociceptive tolerance
AU - Bryant, Leesa
AU - Doyle, Tim
AU - Chen, Zhoumo
AU - Cuzzocrea, Salvatore
AU - Masini, Emanuela
AU - Vinci, M. Cristina
AU - Esposito, Emanuela
AU - Mazzon, Emanuela
AU - Petrusca, Daniela Nicoleta
AU - Petrache, Irina
AU - Salvemini, Daniela
PY - 2009/9/29
Y1 - 2009/9/29
N2 - 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.
AB - 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.
KW - Ceramide
KW - Morphine tolerance
KW - Neuronal apoptosis
KW - Nitroxidative stress
KW - Peroxynitrite
UR - http://www.scopus.com/inward/record.url?scp=68149098861&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=68149098861&partnerID=8YFLogxK
U2 - 10.1016/j.neulet.2009.07.051
DO - 10.1016/j.neulet.2009.07.051
M3 - Article
C2 - 19631718
AN - SCOPUS:68149098861
VL - 463
SP - 49
EP - 53
JO - Neuroscience Letters
JF - Neuroscience Letters
SN - 0304-3940
IS - 1
ER -