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,Chi Wai Cheung,Xinyue Huo,Zhengyuan Xia,Tingting Fan,Jian Cui

doi:10.1155/2019/4856156

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.

Highlights

Diabetes is an increasingly common chronic global epidemic, and relevant neuropathy is its most common and disabling complication
And intriguingly, the total number of diabetic rats that demonstrated Diabetic neuropathic pain (DNP) peaked at 1 week after diabetic induction, and the percentage of diabetic rats that had DNP decreased from 89% to 42% in paw withdrawal threshold (PWT) and from 84% to 52% in paw withdrawal latencies (PWL)
To look into the mechanism that might be attributable to the reduced thresholds of mechanical allodynia and heat hyperalgesia during the earlier phase of diabetes, we further investigated the status of TNF-α and CXCR4 protein expression over time in the dorsal root ganglia (DRG) in addition to that in the spinal cord

Summary

Introduction

Diabetes is an increasingly common chronic global epidemic, and relevant neuropathy is its most common and disabling complication. 20-30% of diabetic patients develop neuropathic pain, and the major clinical manifestations are spontaneous pain, hyperalgesia, and allodynia [2, 3]. These symptoms are the consequences of peripheral (e.g., dorsal root ganglia (DRG)) and/or central (e.g., spinal cord dorsal) sensitization to noxious stimuli. More objective measuring instruments are needed to distinguish mechanical allodynia and heat hyperalgesia in a rodent DNP model [10, 11]. With the development of advanced neuropathic pain, followed by the loss of sensory function or tactile hypoesthesia [12,13,14], mechanical allodynia and heat hyperalgesia cannot be accurately measured by Von Frey and Hargreaves Apparatus. The limitations of behavioral test exist in the animal model were inevitable [15, 16]

Methods

Results

Conclusion