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. 2019 Mar 14:2019:4856156.
doi: 10.1155/2019/4856156. eCollection 2019.

Progressive Increase of Inflammatory CXCR4 and TNF-Alpha in the Dorsal Root Ganglia and Spinal Cord Maintains Peripheral and Central Sensitization to Diabetic Neuropathic Pain in Rats

Dan Zhu  1 , Tingting Fan  2 , Xinyue Huo  3 , Jian Cui  1 , Chi Wai Cheung  2 , Zhengyuan Xia  2
Affiliations

Progressive Increase of Inflammatory CXCR4 and TNF-Alpha in the Dorsal Root Ganglia and Spinal Cord Maintains Peripheral and Central Sensitization to Diabetic Neuropathic Pain in Rats

Dan Zhu et al. Mediators Inflamm. .

Abstract

Diabetic neuropathic pain (DNP) is a common and serious complication of diabetic patients. The pathogenesis of DNP is largely unclear. The proinflammation proteins, CXCR4, and TNF-α play critical roles in the development of pain, while their relative roles in the development of DNP and especially its progression is unknown. We proposed that establishment of diabetic pain models in rodents and evaluating the stability of behavioral tests are necessary approaches to better understand the mechanism of DNP. In this study, Von Frey and Hargreaves Apparatus was used to analyze the behavioral changes of mechanical allodynia and heat hyperalgesia in streptozotocin-induced diabetic rats at different phases of diabetes. Moreover, CXCR4 and TNF-α of spinal cord dorsal and dorsal root ganglia (DRG) were detected by western blotting and immunostaining over time. The values of paw withdrawal threshold (PWT) and paw withdrawal latencies (PWL) were reduced as early as 1 week in diabetic rats and persistently maintained at lower levels during the progression of diabetes as compared to control rats that were concomitant with significant increases of both CXCR4 and TNF-α protein expressions in the DRG at 2 weeks and 5 weeks (the end of the experiments) of diabetes. By contrast, CXCR4 and TNF-α in the spinal cord dorsal horn did not significantly increase at 2 weeks of diabetes while both were significantly upregulated at 5 weeks of diabetes. The results indicate that central sensitization of spinal cord dorsal may result from persistent peripheral sensitization and suggest a potential reference for further treatment of DNP.

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Figures

Figure 1
Figure 1
Timeline of experiment protocol. BL = baseline; w = week; PWT = paw withdrawal threshold; PWL = paw withdrawal latencies.
Figure 2
Figure 2
Variations of PWT (a) and PWL (b) during the progression of STZ-induced diabetes (Dia) in rats. PWT and PWL were significantly decreased from 1 week to 5 weeks as detected by electronic Von Frey and Hargreaves test. All results are presented as means ± SD, n = 19/group, ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, Dia vs. control.
Figure 3
Figure 3
STZ-induced DNP increased the spinal cord dorsal CXCR4 and TNF-α of spinal cord dorsal horn at 5 weeks but not at 2 weeks of diabetes. (a, b) CXCR4 and TNF-α expression in spinal cord dorsal horn, as shown by western blotting, at 2 and 5 weeks after intravenous STZ and control. (c, d) Quantification of CXCR4 and TNF-α in spinal cord. The western blot results are presented as means ± SD (∗P < 0.05, compared with control group, Student's t-test, n = 6/group).
Figure 4
Figure 4
DNP did not significantly increase the expression of CXCR4 and TNF-α in the spinal cord dorsal horn at 2 weeks of diabetes. Confocal images in the spinal cord dorsal horn CXCR4 ((a), A-F) and TNF-α ((b), A-F) after intravenous STZ injection show no significant differences at 2 weeks. C and F are merged images A and B, D and E. Quantification of CXCR4 (c) and TNF-α 2 weeks (d) immunofluorescence intensity (n = 6/group. All data are presented as means ± SD).
Figure 5
Figure 5
DNP significantly increased the expression of CXCR4 and TNF-α in the spinal cord dorsal horn at 5 weeks of diabetes. Immunostaining for CXCR4 ((a), A–F) and TNF-α ((b), A–F) of the spinal cord dorsal horn was measured at 5 weeks after STZ-induced diabetes. Quantitative analysis of CXCR4 and TNF-α of the intensity at 5 weeks. ∗P < 0.05, compared with control group. n = 6/group. All data are presented as means ± SD.
Figure 6
Figure 6
Persistent upregulation of correlative proinflammatory protein TNF-α and CXCR4 in the DRG in rats with DNP both at 2 weeks and at 5 weeks of diabetes. (a, b) Western blot showed the protein expression of CXCR4 and TNF-α in DRG at 2 and 5 weeks. (c, d) Quantitative analysis of CXCR4 and TNF-α in DRG at 2 weeks (c) and 5 weeks (d) of diabetes. All the data are presented as means ± SD (∗P < 0.05, compared with the control group, n = 6/group). DRG = dorsal root ganglion.
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