Spinal ceramide and neuronal apoptosis in morphine antinociceptive tolerance.
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.
Bryant
Leesa
L
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO 63104, USA.
Doyle
Tim
T
Chen
Zhoumo
Z
Cuzzocrea
Salvatore
S
Masini
Emanuela
E
Vinci
M Cristina
MC
Esposito
Emanuela
E
Mazzon
Emanuela
E
Petrusca
Daniela Nicoleta
DN
Petrache
Irina
I
Salvemini
Daniela
D
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis; D002518:Ceramides / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004789:Enzyme Activation; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
D000701:Analgesics, Opioid; D002518:Ceramides; D009020:Morphine; D010088:Oxidoreductases; C108138:dihydroceramide desaturase