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Please use this identifier to cite or link to this item: http://hdl.handle.net/10481/30783

Title: Genetic inactivation and pharmacological blockade of sigma-1 receptors prevent paclitaxel-induced sensory-nerve mitochondrial abnormalities and neuropathic pain in mice
Authors: Nieto López, Francisco Rafael
Cendán Martínez, Cruz Miguel
Cañizares, Francisco J.
Cubero Sánchez, María Angustias
Vela, José M.
Fernández Segura, Eduardo
Baeyens Cabrera, José Manuel
Issue Date: 2014
Abstract: Background Paclitaxel, a widely-used antineoplastic drug, produces a painful peripheral neuropathy that in rodents is associated with peripheral-nerve mitochondrial alterations. The sigma-1 receptor (σ1R) is a ligand-regulated molecular chaperone involved in mitochondrial calcium homeostasis and pain hypersensitivity. This receptor plays a key role in paclitaxel-induced neuropathic pain, but it is not known whether it also modulates mitochondrial abnormalities. In this study, we used a mouse model of paclitaxel-induced neuropathic pain to test the involvement of the σ1R in the mitochondrial abnormalities associated with paclitaxel, by using genetic (σ1R knockout mice) and pharmacological (σ1R antagonist) approaches.
Results Paclitaxel administration to wild-type (WT) mice produced cold- and mechanical-allodynia, and an increase in the frequency of swollen and vacuolated mitochondria in myelinated A-fibers, but not in C-fibers, of the saphenous nerve. Behavioral and mitochondrial alterations were marked at 10 days after paclitaxel-administration and had resolved at day 28. In contrast, paclitaxel treatment did not induce allodynia or mitochondrial abnormalities in σ1R knockout mice. Moreover, the prophylactic treatment of WT mice with BD-1063 also prevented the neuropathic pain and mitochondrial abnormalities induced by paclitaxel.
Conclusions These results suggest that activation of the σ1R is necessary for development of the sensory nerve mitochondrial damage and neuropathic pain produced by paclitaxel. Therefore, σ1R antagonists might have therapeutic value for the prevention of paclitaxel-induced neuropathy.
Sponsorship: This study was partially supported by grant P11-CTS-7649 and grant CTS-109 from Junta de Andalucía, FEDER funds, a grant from Esteve, and a grant from the Centro para el Desarrollo Tecnológico Industrial (NeoGenius Pharma project). F. R. Nieto was supported by a FPU grant from the Spanish Ministerio de Educación y Ciencia (MEC) and C. M. Cendán by the Research Program of the University of Granada.
Publisher: Biomed Central
Keywords: Paclitaxel
Sigma-1 receptors
Chemotherapy-induced peripheral neuropathy
BD-1063
Mitochondria
Allodynia
Neuropathic pain
Sigma-1 receptor knockout mice
URI: http://hdl.handle.net/10481/30783
ISSN: 1744-8069
Rights : Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License
Citation: Nieto, F.R.; et al. Genetic inactivation and pharmacological blockade of sigma-1 receptors prevent paclitaxel-induced sensory-nerve mitochondrial abnormalities and neuropathic pain in mice. Molecular Pain, 10: 11 (2014). [http://hdl.handle.net/10481/30783]
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