Spinal ceramide modulates the development of morphine antinociceptive tolerance via peroxynitrite-mediated nitroxidative stress and neuroimmune activation

Michael M. Ndengele, Salvatore Cuzzocrea, Emanuela Masini, M. Cristina Vinci, Emanuela Esposito, Carolina Muscoli, Daniela Nicoleta Petrusca, Vincenzo Mollace, Emanuela Mazzon, Dechun Li, Irina Petrache, George M. Matuschak, Daniela Salvemini

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)64-75
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume329
Issue number1
DOIs
StatePublished - Apr 1 2009

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Peroxynitrous Acid
Ceramides
Morphine
Sphingomyelin Phosphodiesterase
Opioid Analgesics
Opiate Alkaloids
Serine C-Palmitoyltransferase
Pain
Interleukin-1
Neuroglia
Chronic Pain
Interleukin-6
Spinal Cord
Tumor Necrosis Factor-alpha
Pharmacology
Acids
Enzymes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Spinal ceramide modulates the development of morphine antinociceptive tolerance via peroxynitrite-mediated nitroxidative stress and neuroimmune activation. / Ndengele, Michael M.; Cuzzocrea, Salvatore; Masini, Emanuela; Vinci, M. Cristina; Esposito, Emanuela; Muscoli, Carolina; Petrusca, Daniela Nicoleta; Mollace, Vincenzo; Mazzon, Emanuela; Li, Dechun; Petrache, Irina; Matuschak, George M.; Salvemini, Daniela.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 329, No. 1, 01.04.2009, p. 64-75.

Research output: Contribution to journalArticle

Ndengele, Michael M. ; Cuzzocrea, Salvatore ; Masini, Emanuela ; Vinci, M. Cristina ; Esposito, Emanuela ; Muscoli, Carolina ; Petrusca, Daniela Nicoleta ; Mollace, Vincenzo ; Mazzon, Emanuela ; Li, Dechun ; Petrache, Irina ; Matuschak, George M. ; Salvemini, Daniela. / Spinal ceramide modulates the development of morphine antinociceptive tolerance via peroxynitrite-mediated nitroxidative stress and neuroimmune activation. In: Journal of Pharmacology and Experimental Therapeutics. 2009 ; Vol. 329, No. 1. pp. 64-75.
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