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The possible involvement of JNK activation in the spinal dorsal horn in bortezomib-induced allodynia: the role of TNF-α and IL-1β

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Abstract

Purpose

Bortezomib (BTZ), a widely used chemotherapeutic drug, is closely associated with the development of painful peripheral neuropathy, but the mechanism underlying the induction of this disorder by BTZ remains largely unclear. To examine this association, we have evaluated the activation of mitogen-activated protein kinase (MAPK) family members in the spinal dorsal horn and the role of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) in BTZ-induced allodynia in rats.

Methods

Male Sprague–Dawley rats were used as the model animals. The paw withdrawal test, in which mechanical stimuli (von Frey hairs) is applied to the plantar surface of the hindpaw, was used to determine any changes in the paw withdrawal threshold of the treated rats. A PE-10 catheter was placed intrathecally to deliver TNF-α neutralizing antibody, IL-1 receptor antagonist (IL-1ra) or the c-Jun N-terminal kinase (JNK) inhibitor SP600125. The mRNA levels of various cytokines were measured by real-time quantitative PCR. The expression of TNF-α, IL-1β and mitogen-activated protein kinase (MAPK) family members in the spinal dorsal horn was measured by western blot analysis and immunohistochemistry. All data were expressed as the mean ± standard error of the mean and analyzed using the SPSS version 13.0 software program.

Results

The BTZ treatment induced an upsurge in the mRNA and protein levels of TNF-α in the neurons and IL-1β in the astrocytes in the spinal dorsal horn. It also significantly upregulated the phosphorylation of JNK but not of extracellular signal-regulated kinases (ERK) and p38-MAPK in astrocytes of the spinal dorsal horn. Inhibition of TNF-α or IL-1β ameliorated JNK activation and mechanical allodynia induced by BTZ. Co-administration of thalidomide (TNF-α synthesis inhibitor) and IL-1ra prevented BTZ-induced mechanical allodynia.

Conclusion

Our results suggest that the TNF-α or IL-1β/JNK pathway in the spinal dorsal horn may play a critical role in the development of painful peripheral neuropathy induced by BTZ.

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Acknowledgments

This study was funded by National Natural Science Foundation of China (31171034, 81271474, U1201223 and 81500948), Fundamental Research Funds for the Central Universities (NO.12ykpy03), Program for New Century Excellent Talents in University (NCET-12-0568) and Science and Technology Project in Guangzhou (2014J4100180).

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    Authors and Affiliations

    1. Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yet-Sen University, 74 Zhongshan Rd. 2, Guangzhou, 510080, China

      Yuan-Pei Zhang, Jie Zhang, Su-Bo Zhang, Dai Li, Zhen-Zhen Huang & Wen-Jun Xin

    2. Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-sen University, Sun Yet-Sen University, 58 Zhongshan Rd. 2, Guangzhou, 510080, China

      Zhen-Yu Li

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    Z.-Y. Li and Y.-P. Zhang contributed equally to this work.

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    Li, ZY., Zhang, YP., Zhang, J. et al. The possible involvement of JNK activation in the spinal dorsal horn in bortezomib-induced allodynia: the role of TNF-α and IL-1β. J Anesth 30, 55–63 (2016). https://doi.org/10.1007/s00540-015-2077-x

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