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Perez-Alvarez S, Solesio ME, Cuenca-Lopez MD, et al. Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone. Int J Cell Biol. 2012;2012:642482doi: 10.1155/2012/642482.
Perez-Alvarez, S., Solesio, M. E., Cuenca-Lopez, M. D., Melero-Fernández de Mera, R. M., Villalobos, C., Kmita, H., Galindo, M. F., & Jordán, J. (2012). Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone. International journal of cell biology, 2012642482. https://doi.org/10.1155/2012/642482
Perez-Alvarez, Sergio, et al. "Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone." International journal of cell biology vol. 2012 (2012): 642482. doi: https://doi.org/10.1155/2012/642482
Perez-Alvarez S, Solesio ME, Cuenca-Lopez MD, Melero-Fernández de Mera RM, Villalobos C, Kmita H, Galindo MF, Jordán J. Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone. Int J Cell Biol. 2012;2012:642482. doi: 10.1155/2012/642482. Epub 2012 Jun 17. PMID: 22778742; PMCID: PMC3385639.
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Int J Cell Biol. 2012;2012:642482. doi: 10.1155/2012/642482. Epub 2012 Jun 17.

Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone.

International journal of cell biology

Sergio Perez-Alvarez, Maria E Solesio, Maria D Cuenca-Lopez, Raquel M Melero-Fernández de Mera, Carlos Villalobos, Hanna Kmita, Maria F Galindo, Joaquin Jordán

Affiliations

  1. Neuropharmacology, Department of Medical Sciences, School of Medicine, University of Castilla-La Mancha (UCLM), 02006 Albacete, Spain.

PMID: 22778742 PMCID: PMC3385639 DOI: 10.1155/2012/642482

Abstract

Previously, we have shown that SH-SY5Y cells exposed to high concentrations of methadone died due to a necrotic-like cell death mechanism related to delayed calcium deregulation (DCD). In this study, we show that, in terms of their Ca(2+) responses to 0.5 mM methadone, SH-SY5Y cells can be pooled into four different groups. In a broad pharmacological survey, the relevance of different Ca(2+)-related mechanisms on methadone-induced DCD was investigated including extracellular calcium, L-type Ca(2+) channels, μ-opioid receptor, mitochondrial inner membrane potential, mitochondrial ATP synthesis, mitochondrial Ca(2+)/2Na(+)-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(2+) dyshomeostasis suggesting that methadone induces DCD by modulating the ability of mitochondria to handle Ca(2+). 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(2+) uptake in a respiratory substrate-dependent way. We conclude that methadone causes failure of intracellular Ca(2+) 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.

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