Methadone induces necrotic-like cell death in SH-SY5Y cells by an impairment of mitochondrial ATP synthesis

Methadone is a widely used therapeutic opioid in narcotic addiction and neuropathic pain syndromes. Oncologists regularly use methadone as a long-lasting analgesic. Recently it has also been proposed as a promising agent in leukemia therapy, especially when conventional therapies are not effective Nevertheless, numerous reports indicate a negative impact on human cognition with chronic exposure to opiates Thus, clarification of methadone toxicity is required. In SH-SY5Y cells we found that high concentrations of methadone were required to Induce cell death. Methadone-induced cell death seems to be related to necrotic processes rather than typical apoptosis Cell cultures challenged with methadone presented alterations in mitochondria! outer membrane permeability. A mechanism that involves Bax translocation to the mitochondria was observed, accompanied with cytochrome c release. Furthermore, no participation of known protein regulators of apoptosis such as Bcl-X-L and p53 was observed. Interestingly, methadone-induced cell death took place by a caspases-independent pathway; perhaps due to its ability to induce a drastic depletion in cellular ATP levels. Therefore. we studied the effect of methadone on isolated rat liver mitochondria. We observed that methadone caused mitochondrial uncoupling, coinciding with the ionophoric properties of methadone. but did not cause swelling of the organelles Overall, the effects observed for cells in the presence of supratherapeutic doses of methadone may result from a bioenergetic crisis. A decreased level of cellular energy may predispose cells to necrotic-like cell death. (C) 2010 Elsevier B.V. All rights reserved