Central Endothelial-1 Produces Analgesic Function by Triggering Spinal Neuronal Histone Deacetylase 5 (HDAC5) Nucleocytoplasmic Shuttling Under Neuropathic Pain

Abstract

Objectives: Neuropathic pain has a considerable impact onpatients’ quality of life, which the mechanism is still elusive.Previously, we reported that central administration of endothe-lial- 1(ET-1) attenuated neuropathic pain, while the rationalesare still unclear. it was reported that ET-1, via kinase activationand HDAC5 phosphorylation, promotes nucleocytoplasmicshuttling of HDAC5 in myocytes, which lead to the activationof HDAC5-dependent cascades. In this study, we aimed toinvestigate whether central ET-1 produces anti-nociceptionrole by triggering HDAC5 nucleocytoplasmic shuttling underneuropathic pain. Methods: ET-1 astrocytic overexpression (GET-1) transgenicmice and C57BL/6N mice were subjected to partial sciaticnerve ligation (pSNL). ET-1 peptide, agonist and antagonist ofEndothelial A receptor (ETAR) and ERK, adeno-associatedviruses of wild type and mutant HDAC5 (AAV-HDAC5-WTand AAV-HDAC5-Mut) and behavioral tests, were employedto determine the role of HDAC5 shuttling in ET-1-induced painrelief. Biochemical analysis were used to explore the ET-1/ETAR-HDAC5 dependent pathway in vitro and in vivo.Results: GET-1 mice transfected by AAV-HDAC5-WTinduced the shuttling of phosphorylated-HDAC5 (p-HDAC5ser498) in cytoplasm of spinal dorsal neurons and increasedspinal dorsal GAD 65, which was reversed by ETAR antagonistand ERK inhibitor. These results were confirmed by AAV-HDAC5-Mut virus infected GET-1 mice which showed moremechanical allodynia and thermal hypersensitivity than AAV-HDAC5-WT GET-1 mice. P-HDAC5 was accumulated inspinal neuronal nucleus and GAD 65 decreased in GET-1 micewith AAV-HDAC5-Mut. Conclusions: In this study, we demonstrated that centraladministration of ET-1 increases GAD65 expression viainducing HDAC5 nucleocytoplasmic shuttling to alleviateneuropathic pain processing.