The Chinese Medicine Wu-Tou Decoction Relieves Neuropathic Pain by Inhibiting Hippocampal Microglia Activation

Chunyan Zhu,Qionghong Xu,Na Lin,Zhiyun Mao

doi:10.1038/s41598-018-30006-7

Abstract

The comorbidity between the nociceptive and mental syndromes adds to the refractoriness of neuropathic pain (NP). Wu-Tou decoction (WTD) has been prescribed for chronic pain for thousands of years in China. Recently, we reported that WTD was helpful for hippocampus and co-curative for the nociceptive, depressive and anxiety behaviors in the spinal cord ligation (SNL) mice. However, the mechanism underlying the rescue of hippocampus, as well as the roles hippocampus assumed in co-curation remain unexplored. In this study, we validated that in SNL mice, the long-lasting damages to limbic system were mainly limited to hippocampus. In addition, hippocampal neurons were proven sensitive to harms induced by microglia and rescued by WTD, which in sum indicated hippocampal microglia as the critical modulator of co-curation. To validate this hypothesis the hippocampal microglia were mal-activated in shamed mice, in which the atrophy of hippocampus and the development of NP syndromes were consolidated and proven rescued by WTD. On the contrary, in the SNL mice, the failure to control hippocampal microglia was sufficient to void all the rescues mediated by WTD. In sum, our study points out that the effective modulation of microglia in hippocampus is of pivotal importance for the co-curation by WTD.

Highlights

Multiple studies focusing on the mechanism of comorbidity propose that chronic pain is a maladaptive neuropathological disease state, in which the alternations of the activities and circuitries between brain nuclei in sum contribute to the addition to pain[5]
The atrophy of limbic system in spinal cord ligation (SNL) mice was found long-lasting in hippocampus and rescued by Wu-Tou decoction (WTD)
To clarify the brain nuclei, especially nuclei of the limbic system, responsible for the comorbidity and co-curation in neuropathic pain (NP), the morphological atrophy and remission in anterior cingulate cortex (ACC), basolateral amygdala (BLA), CA1 and CA3 were analyzed by Golgi staining

Summary

Introduction

Multiple studies focusing on the mechanism of comorbidity propose that chronic pain is a maladaptive neuropathological disease state, in which the alternations of the activities and circuitries between brain nuclei in sum contribute to the addition to pain[5]. The up-regulation of tumor necrosis factor alpha (TNFα), secreted by the activated microglia in hippocampus, have been widely recognized as the linker between the comorbidity of chronic pain and the emotional syndromes[13]. The TNFR1 receptor has been proven essential for the development of depressive syndromes in NP animals[18] Both the down-regulation of TNFα by antibodies and the inhibition of TNFα receptors by antagonist were reckoned effective in the remission of pain and depression[19,20]. The commercialized drugs such as infliximab and etanercept have been clinically applied in arthritis and proven effective for the depressive symptoms for a subtype of patients characterized by the elevated expression of inflammatory factors in the blood[21,22]

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Conclusion