Histone Deacetylase 5 (Hdac5) Regulates Neuropathic Pain through SRY-Related HMG-Box 10 (SOX10)-Dependent Mechanism in Mice

Abstract

A strong link between histone deacetylases (HDACs) and nociceptive hypersensitivity has been indicated in different pain models. However, the underlying molecular and cellular mechanisms remain elusive. Here, we discovered that partial sciatic nerve ligation–induced mechanical allodynia and thermal hyperalgesia in mice were associated with increased mRNA and protein expressions of HDAC5 (a member of class IIa HDACs) and SRY-related HMG-box 10 (SOX10) in the ipsilateral lumbar dorsal horn. Gene knockdown of spinal HDAC5 or SOX10 attenuated partial sciatic nerve ligation–induced nociceptive hypersensitivity, companied with decrease of spinal neuronal sensitization markers, namely phosphorylated-Erk, phosphorylated-GluN1 (ser896), and c-Fos. Conversely, overexpression of spinal HDAC5 or SOX10 by lentiviruses in naive mice not only induced pain-like behaviors but also increased the expression of these spinal neuronal sensitization markers. Of note, in contrast to its conventional deacetylation effect to silence gene expression, overexpression of HDAC5 not only enhanced SOX10 expression but also induced nociceptive hypersensitivity in naive mice, which were reversed by SOX10 gene knockdown. Chromatin-immunoprecipitation assay further confirmed a novel nonhistone modulation function of HDACs on SOX10 expression, that is, HDAC5 regulates SOX10 by binding to the promoter region of Sox10 gene. In conclusion, this study for the first time demonstrates that HDAC5 regulates spinal neuronal sensitization in neuropathic pain by upregulating modulating SOX10 expression. Thus, interventions that reduce HDAC5/SOX10 expression may represent promising avenues in the treatment of neuropathic pain.