Central Endothelin-1 Confers Analgesia by Triggering Spinal Neuronal Histone Deacetylase 5 (HDAC5) Nuclear Exclusion in Peripheral Neuropathic Pain in Mice

J Pain. 2021 Apr;22(4):454-471. doi: 10.1016/j.jpain.2020.12.004. Epub 2021 Jan 6.

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.

Keywords: Peripheral neuropathic pain; anti-nociception; endothelin-1; glutamate acid decarboxylases; histone deacetylase 5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesia*
  • Animals
  • Endothelin Receptor Antagonists / administration & dosage
  • Endothelin Receptor Antagonists / pharmacology*
  • Endothelin-1 / drug effects
  • Endothelin-1 / metabolism*
  • Glutamate Decarboxylase / drug effects
  • Glutamate Decarboxylase / metabolism*
  • Histone Deacetylases / drug effects
  • Histone Deacetylases / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuralgia / drug therapy*
  • Neuralgia / metabolism*
  • Peptides, Cyclic / pharmacology

Substances

  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Peptides, Cyclic
  • Hdac5 protein, mouse
  • Histone Deacetylases
  • Glutamate Decarboxylase
  • cyclo(Trp-Asp-Pro-Val-Leu)