title: Spinal ceramide modulates the development of morphine antinociceptive tolerance via peroxynitrite-mediated nitroxidative stress and neuroimmune activation.
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 neuroimmune activation [activation of spinal glial cells and increase formation of tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6]. Inhibition of ceramide biosynthesis with various pharmacological inhibitors significantly attenuated the increase in spinal ceramide production, nitroxidative stress, and neuroimmune 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.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ndengele
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Emanuela
authors.initials: E
authors.lastname: Masini
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Vinci
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Carolina
authors.initials: C
authors.lastname: Muscoli
authors.forename: Daniela Nicoleta
authors.initials: DN
authors.lastname: Petrusca
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mollace
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Dechun
authors.initials: D
authors.lastname: Li
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
authors.forename: George M
authors.initials: GM
authors.lastname: Matuschak
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002518:Ceramides / Q000276:immunology / Q000502:physiology*; D004361:Drug Tolerance; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010088:Oxidoreductases / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism*; D004856:Postural Balance / Q000187:drug effects; D051102:Serine C-Palmitoyltransferase / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D002518:Ceramides; D005904:Glial Fibrillary Acidic Protein; D020672:I-kappa B Proteins; D013109:Sphingomyelins; D030421:Peroxynitrous Acid; D009020:Morphine; D010088:Oxidoreductases; D013482:Superoxide Dismutase; C108138:dihydroceramide desaturase; D051102:Serine C-Palmitoyltransferase; D013108:Sphingomyelin Phosphodiesterase