Affiliation:
1. National Sun Yat-sen University
2. Kaohsiung Armed Forces General Hospital
3. Kaohsiung Medical University
4. Kaohsiung Veterans General Hospital
5. Chang Gung Memorial Hospital Kaohsiung Branch
6. Taipei Veterans General Hospital
Abstract
Abstract
Neuropathic pain (NP) affects countless people worldwide, but there is no effective treatment. Histone deacetylases (HDACs) participate in epigenetic modifications, which are involved in neuropathy-induced nociceptive sensitization. Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter that can inhibit NP. HDACs regulate glutamic acid decarboxylase (GAD) 65 and the production of its downstream metabolite GABA. However, the role of HDACs and their possible cellular mechanisms in the spinal cord in neuropathy remains unclear. We found Hdac3, Hdac4, and Hdac6 gene upregulation in the lumbar spinal cord dorsal horn (SCDH) in chronic constriction injury (CCI) rats by RT-qPCR analysis. By western blotting and immunofluorescence staining, we further confirmed that the HDAC3, HDAC4, and HDAC6 proteins were significantly upregulated, and GAD65 and GABA production decreased dramatically. Intrathecal administration of panobinostat, a non-selective HDAC inhibitor, attenuated nociceptive behavior (thermal hyperalgesia and mechanical allodynia) and restored to downregulated spinal GAD65 and GABA in CCI rats. Thus, the upregulation of HDAC expression might induce nociception through GAD65 and GABA inhibition in CCI-induced neuropathy. These findings strongly suggest that HDACs regulate inhibitory neurotransmitters as a potential therapeutic strategy for an epigenetic approach to managing NP.
Publisher
Research Square Platform LLC