Blocking Potent Oxidant Could Prevent Morphine Tolerance Drugs.com Nov 2008 Blocking a substance called peroxynitrite, a potent oxidant that's formed when patients take morphine, can prevent the development of tolerance to the pain-relieving effects of the narcotic, according to animal tests conducted by Saint Louis University of Medicine researchers. They said their findings, published in the November issue of the Journal of Clinical Investigation, could lead to new therapies that prevent morphine tolerance and the severe side effects caused by having to give patients escalating doses of the painkiller. Morphine and other opiate narcotics are the most powerful treatments for acute and chronic pain. However, their pain-killing effectiveness decreases quickly and significantly with repeated doses. In this study, researchers found that repeated doses of morphine caused peroxynitrite to develop in the spinal cord, resulting in inflammation and damage to proteins and DNA in that area. Putting the brakes on peroxynitrite -- either by causing it to decompose once it formed or by blocking it from forming in the first place -- prevented morphine tolerance. "We believe these findings represent a major breakthrough in understanding how tolerance to the pain-relieving action of morphine and other opiate medications develops -- and how it can be prevented from happening in the first place," study author Daniela Salvemini, a professor of internal medicine in the division of pulmonary, critical care and sleep medicine, said in a prepared statement. This research may help in the development of therapies that enable patients to take morphine without developing tolerance. "For instance, when morphine is administered, another drug could be given simultaneously that prevents peroxynitrite from working and thus causing tolerance to develop," Salvemini explained.For those who want more technical details.
Spinal Ceramide Modulates the Development of Morphine Antinociceptive Tolerance via Peroxynitrite-Mediated Nitroxidative Stress and Neuroimmune Activation Journal of Pharmacology And Experimental Therapeutics Nov 2008 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. 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, and Daniela Salvemini 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.)