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Sirtuin 1 alleviates diabetic neuropathic pain by regulating synaptic plasticity of spinal dorsal horn neurons

Zhang, Zongqina; Ding, Xiaobaoa; Zhou, Zhiweia; Qiu, Zhuanga; Shi, Naihaoa; Zhou, Shashaa; Du, Leia; Zhu, Xiaa; Wu, Yuqingb; Yin, Xiaoxinga; Zhou, Chenghuaa,*

doi: 10.1097/j.pain.0000000000001489
Research Paper
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Accumulating evidence has demonstrated that the enhanced synaptic plasticity of nociceptive interneurons in the spinal dorsal horn is the basis of central sensitization in neuropathic pain. Our previous results demonstrated that sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, alleviates neuropathic pain in type 2 diabetes mellitus rats. SIRT1 has also been reported to regulate synaptic plasticity in different brain neurons. However, the role of SIRT1 in synaptic plasticity of spinal dorsal horn neurons remains unknown. In this study, we found that in the spinal dorsal horn of diabetic neuropathic pain (DNP) rats and db/db mice, decreased SIRT1 expression was accompanied by enhanced structural synaptic plasticity. The levels of postsynaptic density protein 95 (PSD-95), growth-associated protein 43 (GAP43), and synaptophysin increased in the spinal dorsal horn of DNP rats and db/db mice and in high glucose–cultured primary spinal neurons. Upregulation of spinal SIRT1 by SIRT1 activator SRT1720 relieved pain behavior, inhibited the enhanced structural synaptic plasticity in rats and db/db mice with DNP, and decreased the levels of synapse-associated proteins in DNP rats, db/db mice, and high glucose–cultured spinal neurons. SIRT1-shRNA induced pain behavior and enhanced structural synaptic plasticity in normal rats and increased synapse-associated proteins levels in normal rats and spinal neurons. Intrathecal injection of AAV-Cre-EGFP into SIRT1flox/flox mice also induced pain behavior and enhanced synaptic plasticity of the spinal dorsal horn neurons. These results suggest that SIRT1 plays an important role in the progression of DNP by regulating synaptic plasticity of spinal dorsal horn neurons.

SIRT1-mediated change of synaptic plasticity in spinal dorsal horn neurons was involved in the development of diabetic neuropathic pain.

aJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China

bJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China

Corresponding authors. Address: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China. Tel.: +86 516 83262106. E-mail address: chzhou77@xzhmu.edu.cn (C. Zhou).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Z. Zhang, X. Ding, and Z. Zhou contributed equally to this work.

Received September 09, 2018

Received in revised form January 02, 2019

Accepted January 08, 2019

© 2019 International Association for the Study of Pain
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