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NEUROPHARMACOLOGY

Spinal Ceramide Modulates the Development of Morphine Antinociceptive Tolerance via Peroxynitrite-Mediated Nitroxidative Stress and Neuroimmune Activation

Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Saint Louis University School of Medicine, St. Louis, Missouri (M.M.N., D.L., G.M.M., D.S.); Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy (S.C.); Istituto di Ricovero e Cura a Carattere Scientifico Centro Neurolesi "Bonino-Pulejo," Messina, Italy (S.C., E.Mas., E.E.); Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy (M.C.V., E.Maz.); Department of Experimental Pharmacology, University of Naples "Federico II," Naples, Italy (E.E.); Centro di Neurofarmacologia Sperimentale, Istituto di Ricovero e Cura a Carattere Scientifico Mondino-Università Tor Vergata Rome, Rome, Italy (C.M., V.M.); and Indiana University Pulmonary, Allergy, Critical Care, and Occupational Medicine, Indianapolis, Indiana (D.N.P., I.P.)

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-, 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 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.

Address correspondence to: Dr. Daniela Salvemini, Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Saint Louis University School of Medicine, St. Louis, MO. E-mail: salvemd{at}slu.edu