• Sara Marinelli, Francesca Nazio, Antonella Tinari, Laura Ciarlo, Marcello D'Amelio, Luisa Pieroni, Valentina Vacca, Andrea Urbani, Francesco Cecconi, Walter Malorni, and Flaminia Pavone.
• CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, Italy Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy Department of Technology and Health, Istituto Superiore di Sanita', Rome, Italy Department of Therapeutic Research and Medicine Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanita', Rome, Italy Medical School, University Campus-Biomedico, Rome, Italy Department of Experimental Medicine and Surgery, Division of Biochemistry, University of "Tor Vergata", Rome, Italy Dulbecco Telethon Institute, Department of Biology, University of "Tor Vergata", Rome, Italy San Raffaele Institute, Sulmona, L'Aquila, Italy Center of Integrated Metabolomics, Rome, Italy.
• Pain. 2014 Jan 1; 155 (1): 93-107.

AbstractAxonal degeneration in peripheral nerves after injury is accompanied by myelin degradation initiated by Schwann cells (SCs). These cells activate autophagy, a ubiquitous cytoprotective process essential for degradation and recycling of cellular constituents. Concomitantly to nerve insult and axonal degeneration, neuropathic pain (NeP) arises. The role of SC autophagy in the mechanisms underlying NeP is still unknown. In this study, we examined the role of the autophagy during the early phase of Wallerian degeneration in NeP induction and chronification by using a murine model of peripheral nerve lesion (chronic constriction injury). We demonstrate that the autophagy inducer rapamycin, administered in the first week after nerve damage, induces long-lasting analgesic and antiinflammatory effects, facilitates nerve regeneration, and prevents pain chronification. Conversely, when autophagy is altered, by means of autophagic inhibitor 3-methyladenine administration or as occurs in activating molecule in Beclin-1-regulated autophagy transgenic mice (Ambra1(+/gt)), NeP is dramatically enhanced and prolonged. Immunohistochemical and ultrastructural evaluations show that rapamycin is able to increase autophagic flux in SCs, to accelerate myelin compaction, and to reduce inflammatory and immune reaction. Proteomic analysis combined with bioinformatic analysis suggests that a redox-sensitive mechanism could be responsible for SC autophagy activation. These data suggest that a deficiency of autophagic activity in SCs can be an early event in the origin of NeP chronification and that autophagy modulation may represent a powerful pharmacological approach to prevent the onset and chronification of NeP in the clinical setting. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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