TY - JOUR
T1 - Spinal ceramide modulates the development of morphine antinociceptive tolerance via peroxynitrite-mediated nitroxidative stress and neuroimmune activation
AU - Ndengele, Michael M.
AU - Cuzzocrea, Salvatore
AU - Masini, Emanuela
AU - Vinci, M. Cristina
AU - Esposito, Emanuela
AU - Muscoli, Carolina
AU - Petrusca, Daniela Nicoleta
AU - Mollace, Vincenzo
AU - Mazzon, Emanuela
AU - Li, Dechun
AU - Petrache, Irina
AU - Matuschak, George M.
AU - Salvemini, Daniela
PY - 2009/4
Y1 - 2009/4
N2 - The effective treatment of pain is typically limited by a decrease in the pain-relieving action of morphine that follows its chronic administration (tolerance). Therefore, restoring opioid efficacy is of great clinical importance. In a murine model of opioid antinociceptive tolerance, repeated administration of morphine significantly stimulated the enzymatic activities of spinal cord serine palmitoyltransferase, ceramide synthase, and acid sphingomyelinase (enzymes involved in the de novo and sphingomyelinase pathways of ceramide biosynthesis, respectively) and led to peroxynitrite-derive nitroxidative stress and neuro-immune activation [activation of spinal glial cells and increase formation of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6]. Inhibition of ceramide biosynthesis with various pharmacological inhibitors significantly attenuated the increase in spinal ceramide production, nitroxidative stress, and neuroim-mune activation. These events culminated in a significant inhibition of the development of morphine antinociceptive tolerance at doses devoid of behavioral side effects. Our findings implicate ceramide as a key upstream signaling molecule in the development of morphine antinociceptive tolerance and provide the rationale for development of inhibitors of ceramide biosynthesis as adjuncts to opiates for the management of chronic pain.
AB - The effective treatment of pain is typically limited by a decrease in the pain-relieving action of morphine that follows its chronic administration (tolerance). Therefore, restoring opioid efficacy is of great clinical importance. In a murine model of opioid antinociceptive tolerance, repeated administration of morphine significantly stimulated the enzymatic activities of spinal cord serine palmitoyltransferase, ceramide synthase, and acid sphingomyelinase (enzymes involved in the de novo and sphingomyelinase pathways of ceramide biosynthesis, respectively) and led to peroxynitrite-derive nitroxidative stress and neuro-immune activation [activation of spinal glial cells and increase formation of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6]. Inhibition of ceramide biosynthesis with various pharmacological inhibitors significantly attenuated the increase in spinal ceramide production, nitroxidative stress, and neuroim-mune activation. These events culminated in a significant inhibition of the development of morphine antinociceptive tolerance at doses devoid of behavioral side effects. Our findings implicate ceramide as a key upstream signaling molecule in the development of morphine antinociceptive tolerance and provide the rationale for development of inhibitors of ceramide biosynthesis as adjuncts to opiates for the management of chronic pain.
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U2 - 10.1124/jpet.108.146290
DO - 10.1124/jpet.108.146290
M3 - Article
C2 - 19033555
AN - SCOPUS:63849290250
VL - 329
SP - 64
EP - 75
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 1
ER -