Normalizing HDAC2 Levels in the Spinal Cord Alleviates Thermal and Mechanical Hyperalgesia After Peripheral Nerve Injury and Promotes GAD65 and KCC2 Expression

Abstract

Neuropathic pain is a worldwide health concern with poor treatment outcomes. Accumulating evidence suggests that histone hypoacetylation is involved in development and maintenance of neuropathic pain. Thus, many natural and synthetic histone deacetylase (HDACs) inhibitors were tested and exhibited a remarkable analgesic effect against neuropathic pain in animals. However, studies evaluating specific subtypes of HDACs contributing to neuropathic pain are limited. In this study, using the chronic constriction injury (CCI) rat model, we found that mRNA and protein levels of HDAC2 were increased in the lumbar spinal cord of rats after sciatic nerve injury. Intrathecal injection of TSA, a pan-HDAC inhibitor, suppressed the increase in HDAC2 protein but not mRNA, and showed a dose-dependent pain-relieving effect. By introducing HDAC2-specific shRNA into the spinal cord via a lentivirus vector, we confirmed that HDAC2 mediates mechanical and thermal hyperalgesia after nerve injury. Further examination found two essential participants in neuropathic pain in the inhibitory circuit of the central nervous system: GAD65 and KCC2 were increased in the spinal cord of CCI rats after HDAC2 knockdown. Thus, our research confirmed that HDAC2 was involved in mechanical and thermal hyperalgesia induced by peripheral nerve injury. Furthermore, GAD65 and KCC2 were the possible downstream targets of HDAC2 in pain modulation pathways.

17β-Estradiol Attenuates Neuropathic Pain Caused by Spared Nerve Injury by Upregulating CIC-3 in the Dorsal Root Ganglion of Ovariectomized Rats

“…Neuropathic pain is a worldwide health concern with poor treatment outcomes (Norcini et al, 2016; Mo et al, 2018; Ouyang et al, 2019). Increases in spontaneous ectopic discharge in DRG neurons have been shown to play a critical role in neuropathic pain genesis (Mo et al, 2018).…”

“…Thermal hyperalgesia was assessed according to a previously described protocol (Ouyang et al, 2019; Si et al, 2019). The thermal withdrawal latency in response to radiant heat stimulation was measured with an analgesia meter (Ugo Basile, Stoelting, IL, United States).…”

“…Neuropathic pain, a form of allodynia or hyperalgesic spontaneous pain, remains a major challenge for pain researchers and clinicians (Fukuda et al, 2017; Xu et al, 2017; Zhang et al, 2018; Ouyang et al, 2019). Inflammatory-mediator release at the site of injury triggers alterations in the properties of primary afferent neurons and increases their excitability leading to ectopic, stimulus-independent activity (Colloca et al, 2017; Alles and Smith, 2018).…”

The Role of Astrocytes in the Modulation ofK+-Cl−-Cotransporter-2 Function

“…The first reported instance of a relationship between neuropathic pain and the downregulation of KCC2 was in a rat model of peripheral nerve injury induced by implantation of a polyethylene cuff around the sciatic nerve [ 1 ]. Subsequently, our laboratory and others demonstrated that a sciatic nerve injury induced by other methods exhibited similar results [ 5 , 6 , 7 , 8 ]. The transection of the inferior alveolar nerve could induce neuropathic pain in the orofacial region and decrease KCC2 expression in the trigeminal spinal subnucleus caudalis [ 9 ].…”

Sex‐dependent pronociceptive role of spinal α5‐GABAA receptor and its epigenetic regulation in neuropathic rodents

“…Interestingly, sex hormones, such as E2 and testosterone, have been shown to induce epigenetic modifications and chromatin reorganization (Dkhil et al., 2015; Mourad et al., 2014). Several studies show that epigenetic mechanisms, such as DNA methylation/demethylation, histone modifications, and non‐coding RNAs participate in chronic pain (Hsieh et al., 2016; Laumet et al., 2015; Liang, Lutz, Bekker, & Tao, 2015; Ouyang et al., 2019; Sun et al., 2019; Wang et al., 2011, 2016; Yadav & Weng, 2017; Zhang, Chen, Laumet, Chen, & Pan, 2016; Zhao et al., 2017). DNA methylation consists of the enzymatic transference of a methyl group to the 5’ position of a cytosine, primarily occurring in the CpG dinucleotides in mammals (Costello & Plass, 2001).…”