Spinal Astrocytic Activation Contributes to Mechanical Allodynia in a Rat Chemotherapy-Induced Neuropathic Pain Model

Xi-Tuan Ji,Dong-Sheng Zhao,Jin-Mao Li,Dong Jia,Gang Huang,Peng Wang,Lei Zhang,Nian-Song Qian,Zhou Fei,Le Niu,Tao Zhang,Xin-Kui Li,Ferenc Gallyas

doi:10.1371/journal.pone.0060733

Abstract

Chemotherapy-induced neuropathic pain (CNP) is the major dose-limiting factor in cancer chemotherapy. However, the neural mechanisms underlying CNP remain enigmatic. Accumulating evidence implicates the involvement of spinal glia in some neuropathic pain models. In this study, using a vincristine-evoked CNP rat model with obvious mechanical allodynia, we found that spinal astrocyte rather than microglia was dramatically activated. The mechanical allodynia was dose-dependently attenuated by intrathecal administratration of L-α-aminoadipate (astrocytic specific inhibitor); whereas minocycline (microglial specific inhibitor) had no such effect, indicating that spinal astrocytic activation contributes to allodynia in CNP rat. Furthermore, oxidative stress mediated the development of spinal astrocytic activation, and activated astrocytes dramatically increased interleukin-1β expression which induced N-methyl-D-aspartic acid receptor (NMDAR) phosphorylation in spinal neurons to strengthen pain transmission. Taken together, our findings suggest that spinal activated astrocytes may be a crucial component of the pathophysiology of CNP and “Astrocyte-Cytokine-NMDAR-neuron” pathway may be one detailed neural mechanisms underlying CNP. Thus, inhibiting spinal astrocytic activation may represent a novel therapeutic strategy for treating CNP.

Highlights

Chemotherapy-induced neuropathic pain (CNP) is a common, dose-limiting side effect of cancer chemotherapeutic agents which include the vinca alkaloids such as vincristine
No difference in motor function and plasma levels of aspartate aminotransferase and alanine aminotransferase was observed between Sham group and Vincristine group, and these values maintained at normal level from 1 w to 5 w (Fig. 1B–D)
In contrast with the severe mechanical allodynia, no significant changes in thermal withdrawal thresholds were observed between Sham group (14.561.2 s; 5 w) and Vincristine group (13.261.4 s; 5 w) (Fig. 1F)

Summary

Introduction

Chemotherapy-induced neuropathic pain (CNP) is a common, dose-limiting side effect of cancer chemotherapeutic agents which include the vinca alkaloids such as vincristine. There have been no validated measures for the prevention or treatment of CNP with ambiguous underlying mechanisms. At this point, it might be of critical importance to address the mechanisms of CNP and obtain effective treatment strategies for this devastating disease [3]. Unlike neuropathic pain induced by trauma and diabetes, pain in paclitaxel-treated and vincristine-treated rats occurs in the absence of axonal degeneration in peripheral nerves [4,5], suggesting that the mechanisms underlying CNP are elusive and complex.

Methods

Results

Conclusion