• Pan Gu, Tingting Fan, WongStanley Sau ChingSSCDepartment of Anaesthesiology, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China., Zhiqiang Pan, Wai Lydia Tai, Sookja Kim Chung, and Chi Wai Cheung.
• Department of Anaesthesiology, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China; Department of Anaesthesiology, The University of Hong Kong-Shenzhen Hospital, Guangdong province, China.
• J Pain. 2021 Apr 1; 22 (4): 454-471.

AbstractThe rationale of spinal administration of endothelin-1(ET-1) mediated anti-nociceptive effect has not been elucidated. ET-1 is reported to promote nuclear effluxion of histone deacetylase 5 (HDAC5) in myocytes, and spinal HDAC5 is implicated in modulation of pain processing. In this study, we aimed to investigate whether central ET-1 plays an anti-nociceptive role by facilitating spinal HDAC5 nuclear shuttling under neuropathic pain. Here, we demonstrate that upregulating spinal ET-1 attenuated the nociception induced by partial sciatic nerve ligation surgery and this analgesic effect mediated by ET-1 was attenuated by intrathecal injection of endothelin A receptor selective inhibitor (BQ123) or by blocking the exportation of nuclear HDAC5 by adeno-associated viruses targeting neuronal HDAC5 (AVV-HDAC5 S259/498A Mutant). Notably, ET-1 administration increased spinal glutamate acid decarboxylases (GAD65/67) expression via initiating HDAC5 nuclear exportation and increased the acetylation of histone 3 at lysine 9 (Acetyl-H3K9) in the promotor regions of spinal Gad1 and Gad2 genes. This was reversed by blocking endothelin A receptor function or by inhibiting the spinal neuronal nuclear exportation of HDAC5. Therefore, inducing spinal GABAergic neuronal HDAC5 nuclear exportation may be a novel therapeutic approach for managing neuropathic pain. PERSPECTIVE: Neuropathic pain is intractable in a clinical setting, and epigenetic regulation is considered to contribute to this processing. Characterizing the anti-nociceptive effect of ET-1 and investigating the associated epigenetic mechanisms in animal models may lead to the development of new therapeutic strategies and targets for treating neuropathic pain.Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.

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