Journal
MOLECULAR PAIN
Volume 10, Issue -, Pages -Publisher
SAGE PUBLICATIONS INC
DOI: 10.1186/1744-8069-10-11
Keywords
Paclitaxel; Sigma-1 receptors; Chemotherapy-induced peripheral neuropathy; BD-1063; Mitochondria; Allodynia; Neuropathic pain; Sigma-1 receptor knockout mice
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Funding
- Junta de Andalucia [P11-CTS-7649, CTS-109]
- FEDER funds
- Esteve
- Centro para el Desarrollo Tecnologico Industrial (NeoGenius Pharma project)
- Spanish Ministerio de Educacion y Ciencia (MEC)
- University of Granada
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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 (sigma R-1) 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 sigma R-1 in the mitochondrial abnormalities associated with paclitaxel, by using genetic (sigma R-1 knockout mice) and pharmacological (sigma R-1 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 sigma R-1 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 sigma R-1 is necessary for development of the sensory nerve mitochondrial damage and neuropathic pain produced by paclitaxel. Therefore, sigma R-1 antagonists might have therapeutic value for the prevention of paclitaxel-induced neuropathy.
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