Abstract
The 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.
Key words
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Article info
Publication history
Published online: January 06, 2021
Accepted:
December 14,
2020
Received in revised form:
October 6,
2020
Received:
June 7,
2020
Footnotes
The study was supported by the Department of Anaesthesiology, The University of Hong Kong. And The Young Scientist Fund of National Natural Science Foundation of China (no. 82001196).
The authors have no conflicts of interest to declare.
Identification
Copyright
© 2021 by United States Association for the Study of Pain, Inc.
