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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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.
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.
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.
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.
KeywordsBortezomib TNF-α IL-1β Allodynia c-Jun N-terminal kinase
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).
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interests.
- 1.Zhang H, Boyette-Davis JA, Kosturakis AK, Li Y, Yoon SY, Walters ET, Dougherty PM. Induction of monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 in primary sensory neurons contributes to paclitaxel-induced peripheral neuropathy. J Pain. 2013;14:1031–44.PubMedCentralCrossRefPubMedGoogle Scholar
- 9.Honore P, Wade CL, Zhong CM, Harris RR, Wu C, Ghayur T, Iwakura Y, Decker MW, Faltynek C, Sullivan J, Jarvis MF. Interleukin-1 alpha beta gene-deficient mice show reduced nociceptive sensitivity in models of inflammatory and neuropathic pain but not post-operative pain. Behav Brain Res. 2006;167:355–64.CrossRefPubMedGoogle Scholar
- 11.Wei XH, Zang Y, Wu CY, Xu JT, Xin WJ, Liu XG. Peri-sciatic administration of recombinant rat TNF-alpha induces mechanical allodynia via upregulation of TNF-alpha in dorsal root ganglia and in spinal dorsal horn: the role of NF-kappa B pathway. Exp Neurol. 2007;205:471–84.CrossRefPubMedGoogle Scholar
- 36.Winkelstein BA, Rutkowski MD, Sweitzer SM, Pahl JL, DeLeo JA. Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment. J Comp Neurol. 2001;439:127–39.CrossRefPubMedGoogle Scholar