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Genetic inactivation and pharmacological blockade of sigma-1 receptors prevent paclitaxel-induced sensory-nerve mitochondrial abnormalities and neuropathic pain in mice.

Nieto FR, Cendán CM, Cañizares FJ, Cubero MA, Vela JM, Fernández-Segura E, Baeyens JM - Mol Pain (2014)

Bottom Line: Paclitaxel, a widely-used antineoplastic drug, produces a painful peripheral neuropathy that in rodents is associated with peripheral-nerve mitochondrial alterations.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Biomedical Research Centre and Institute of Neuroscience, University of Granada, 18012 Granada, Spain. efsegura@ugr.es.

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.

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Related in: MedlinePlus

Effects of σ1R blockade in paclitaxel-induced neuropathic pain behaviors. Effect of paclitaxel + saline and paclitaxel-vehicle + saline on the duration of hind paw licking/biting in the acetone test (a) and on the threshold force for hind paw withdrawal in the electronic Von Frey test (b) in WT and σ1R-KO mice. Time-courses of the effect of paclitaxel + saline, paclitaxel + BD-1063 (32 mg/kg), and paclitaxel-vehicle + saline in the acetone test (c) and in the electronic Von Frey test (d) in WT mice. The animals were treated once daily from days 1 to 5 with an i.p. injection of paclitaxel (2 mg/kg) or its vehicle (a,b) and with an s.c. injection of BD-1063 or saline 30 min before each paclitaxel dose (c,d). The response was recorded in each animal 3 days before (PRE) and on days 10 and 28 after the start of treatment. Each point and vertical line represents the mean ± SEM of the values obtained in 6–12 animals. Statistically significant differences between WT mice treated with paclitaxel + saline and the rest of the groups on the same day after treatment, **p < 0.01; and between the values on the pretreatment day and the days after treatment, ## p < 0.01 (two-way repeated measures ANOVA followed by Bonferroni test).
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Figure 1: Effects of σ1R blockade in paclitaxel-induced neuropathic pain behaviors. Effect of paclitaxel + saline and paclitaxel-vehicle + saline on the duration of hind paw licking/biting in the acetone test (a) and on the threshold force for hind paw withdrawal in the electronic Von Frey test (b) in WT and σ1R-KO mice. Time-courses of the effect of paclitaxel + saline, paclitaxel + BD-1063 (32 mg/kg), and paclitaxel-vehicle + saline in the acetone test (c) and in the electronic Von Frey test (d) in WT mice. The animals were treated once daily from days 1 to 5 with an i.p. injection of paclitaxel (2 mg/kg) or its vehicle (a,b) and with an s.c. injection of BD-1063 or saline 30 min before each paclitaxel dose (c,d). The response was recorded in each animal 3 days before (PRE) and on days 10 and 28 after the start of treatment. Each point and vertical line represents the mean ± SEM of the values obtained in 6–12 animals. Statistically significant differences between WT mice treated with paclitaxel + saline and the rest of the groups on the same day after treatment, **p < 0.01; and between the values on the pretreatment day and the days after treatment, ## p < 0.01 (two-way repeated measures ANOVA followed by Bonferroni test).

Mentions: On the pretreatment day, WT and σ1R-KO mice showed a similar duration of acetone-induced paw licking/biting (Figure 1a) and a similar threshold force for paw withdrawal in the electronic Von Frey test (Figure 1b). Treatment with paclitaxel vehicle did not significantly modify the response of WT or σ1R-KO mice in any test at any measurement time point (Figure 1a and b). However, on day 10 after the first paclitaxel injection, WT mice showed a statistically significant increase in acetone-induced paw licking/biting duration (cold-allodynia) and a reduction in threshold force for paw withdrawal in the electronic Von Frey test (mechanical allodynia) (Figure 1a and b). On day 28 after the first paclitaxel dose, the response of WT animals had returned to normal values in both tests (Figure 1a and b). In contrast, the paclitaxel-treated σ1R-KO mice showed no sign of cold or mechanical allodynia at any time point (Figure 1a and b). Likewise, the s.c prophylactic administration of the selective σ1R antagonist BD-1063 (32 mg/kg) to WT animals, totally prevented the development of cold and mechanical allodynia (Figure 1c and d). Therefore, σ1R inhibition induced by genetic inactivation (σ1R-KO mice) or treatment with a selective σ1R antagonist (BD-1063) completely averted the neuropathic pain behavioral manifestations induced by paclitaxel administration.


Genetic inactivation and pharmacological blockade of sigma-1 receptors prevent paclitaxel-induced sensory-nerve mitochondrial abnormalities and neuropathic pain in mice.

Nieto FR, Cendán CM, Cañizares FJ, Cubero MA, Vela JM, Fernández-Segura E, Baeyens JM - Mol Pain (2014)

Effects of σ1R blockade in paclitaxel-induced neuropathic pain behaviors. Effect of paclitaxel + saline and paclitaxel-vehicle + saline on the duration of hind paw licking/biting in the acetone test (a) and on the threshold force for hind paw withdrawal in the electronic Von Frey test (b) in WT and σ1R-KO mice. Time-courses of the effect of paclitaxel + saline, paclitaxel + BD-1063 (32 mg/kg), and paclitaxel-vehicle + saline in the acetone test (c) and in the electronic Von Frey test (d) in WT mice. The animals were treated once daily from days 1 to 5 with an i.p. injection of paclitaxel (2 mg/kg) or its vehicle (a,b) and with an s.c. injection of BD-1063 or saline 30 min before each paclitaxel dose (c,d). The response was recorded in each animal 3 days before (PRE) and on days 10 and 28 after the start of treatment. Each point and vertical line represents the mean ± SEM of the values obtained in 6–12 animals. Statistically significant differences between WT mice treated with paclitaxel + saline and the rest of the groups on the same day after treatment, **p < 0.01; and between the values on the pretreatment day and the days after treatment, ## p < 0.01 (two-way repeated measures ANOVA followed by Bonferroni test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: Effects of σ1R blockade in paclitaxel-induced neuropathic pain behaviors. Effect of paclitaxel + saline and paclitaxel-vehicle + saline on the duration of hind paw licking/biting in the acetone test (a) and on the threshold force for hind paw withdrawal in the electronic Von Frey test (b) in WT and σ1R-KO mice. Time-courses of the effect of paclitaxel + saline, paclitaxel + BD-1063 (32 mg/kg), and paclitaxel-vehicle + saline in the acetone test (c) and in the electronic Von Frey test (d) in WT mice. The animals were treated once daily from days 1 to 5 with an i.p. injection of paclitaxel (2 mg/kg) or its vehicle (a,b) and with an s.c. injection of BD-1063 or saline 30 min before each paclitaxel dose (c,d). The response was recorded in each animal 3 days before (PRE) and on days 10 and 28 after the start of treatment. Each point and vertical line represents the mean ± SEM of the values obtained in 6–12 animals. Statistically significant differences between WT mice treated with paclitaxel + saline and the rest of the groups on the same day after treatment, **p < 0.01; and between the values on the pretreatment day and the days after treatment, ## p < 0.01 (two-way repeated measures ANOVA followed by Bonferroni test).
Mentions: On the pretreatment day, WT and σ1R-KO mice showed a similar duration of acetone-induced paw licking/biting (Figure 1a) and a similar threshold force for paw withdrawal in the electronic Von Frey test (Figure 1b). Treatment with paclitaxel vehicle did not significantly modify the response of WT or σ1R-KO mice in any test at any measurement time point (Figure 1a and b). However, on day 10 after the first paclitaxel injection, WT mice showed a statistically significant increase in acetone-induced paw licking/biting duration (cold-allodynia) and a reduction in threshold force for paw withdrawal in the electronic Von Frey test (mechanical allodynia) (Figure 1a and b). On day 28 after the first paclitaxel dose, the response of WT animals had returned to normal values in both tests (Figure 1a and b). In contrast, the paclitaxel-treated σ1R-KO mice showed no sign of cold or mechanical allodynia at any time point (Figure 1a and b). Likewise, the s.c prophylactic administration of the selective σ1R antagonist BD-1063 (32 mg/kg) to WT animals, totally prevented the development of cold and mechanical allodynia (Figure 1c and d). Therefore, σ1R inhibition induced by genetic inactivation (σ1R-KO mice) or treatment with a selective σ1R antagonist (BD-1063) completely averted the neuropathic pain behavioral manifestations induced by paclitaxel administration.

Bottom Line: Paclitaxel, a widely-used antineoplastic drug, produces a painful peripheral neuropathy that in rodents is associated with peripheral-nerve mitochondrial alterations.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Biomedical Research Centre and Institute of Neuroscience, University of Granada, 18012 Granada, Spain. efsegura@ugr.es.

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.

Show MeSH
Related in: MedlinePlus