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In this study, we show that, in terms of their Ca<jats:sup>2+<\/jats:sup>responses to 0.5\u2009mM methadone, SH-SY5Y cells can be pooled into four different groups. In a broad pharmacological survey, the relevance of different Ca<jats:sup>2+<\/jats:sup>-related mechanisms on methadone-induced DCD was investigated including extracellular calcium, L-type Ca<jats:sup>2+<\/jats:sup>channels,<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\"><mml:mi>\u03bc<\/mml:mi><\/mml:math>-opioid receptor, mitochondrial inner membrane potential, mitochondrial ATP synthesis, mitochondrial Ca<jats:sup>2+<\/jats:sup>\/2Na<jats:sup>+<\/jats:sup>-exchanger, reactive oxygen species, and mitochondrial permeability transition. Only those compounds targeting mitochondria such as oligomycin, FCCP, CGP 37157, and cyclosporine A were able to amend methadone-induced Ca<jats:sup>2+<\/jats:sup>dyshomeostasis suggesting that methadone induces DCD by modulating the ability of mitochondria to handle Ca<jats:sup>2+<\/jats:sup>. Consistently, mitochondria became dramatically shorter and rounder in the presence of methadone. Furthermore, analysis of oxygen uptake by isolated rat liver mitochondria suggested that methadone affected mitochondrial Ca<jats:sup>2+<\/jats:sup>uptake in a respiratory substrate-dependent way. We conclude that methadone causes failure of intracellular Ca<jats:sup>2+<\/jats:sup>homeostasis, and this effect is associated with morphological and functional changes of mitochondria. Likely, this mechanism contributes to degenerative side effects associated with methadone treatment.<\/jats:p>","DOI":"10.1155\/2012\/642482","type":"journal-article","created":{"date-parts":[[2012,6,18]],"date-time":"2012-06-18T02:49:44Z","timestamp":1339987784000},"page":"1-8","source":"Crossref","is-referenced-by-count":3,"title":["Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone"],"prefix":"10.1155","volume":"2012","author":[{"given":"Sergio","family":"Perez-Alvarez","sequence":"first","affiliation":[{"name":"Neuropharmacology, Department of Medical Sciences, School of Medicine, University of Castilla-La Mancha (UCLM), 02006 Albacete, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E.","family":"Solesio","sequence":"additional","affiliation":[{"name":"Translational Neuropsychopharmacology Unit, Albacete University Hospital Center, Albacete, 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