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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 (σ 1 R) 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 σ 1 R in the mitochondrial abnormalities associated with paclitaxel, by using genetic (σ 1 R knockout mice) and pharmacological (σ 1 R 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 σ 1 R 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 σ 1 R is necessary for development of the sensory nerve mitochondrial damage and neuropathic pain produced by paclitaxel. Therefore, σ 1 R antagonists might have therapeutic value for the prevention of paclitaxel-induced neuropathy.

molecular pain

Genetic Inactivation and Pharmacological Blockade of Sigma-1 Receptors Prevent Paclitaxel-Induced Sensory-Nerve Mitochondrial Abnormalities and Neuropathic Pain in Mice