The epigenetic regulations in peripheral neuropathic pain in mice

Abstract

Accumulating evidence implicates epigenetic modifications are associated with nociceptive hypersensitivity induced by different pain models. Although central sensitization is indicated to presents the over-excitability of sensory neurons, abnormal synaptic efficacy and the loss of GABA inhibition tone, which contributes to the pain processes. But, the underlying molecular and cellular mechanisms remain elusive.

This thesis aims to investigate the epigenetic regulation mechanisms of three key components of central sensitization under a peripheral nerve injury animal model. In Chapter 3, we discovered that overexpressed spinal histone deacetylase 5 (HDAC5) contributed to the spinal neurons sensitization in a SRY-related HMG-box 10 (SOX10)-dependent way. Manipulate spinal HDAC5 as well as SOX10 attenuated the nociception induced pSNL surgery. Thus, knocking down HDAC5 and SOX10 may represent promising therapeutic targets in the treatment of neuropathic pain.

In Chapter 4, we implicated that endothelin-1(ET-1) mediated the spinal HDAC5 nuclear effluxion by activating the protein kinase C (PKC ) increase the spinal glutamate decarboxylase 65 (GAD 65) and GAD67 expressions and attenuated the nociception induced by nerve injury. This study reveals the regulatory roles of epigenetic modulations in spinal GABAergic inhibitory. Therefore, the increase the nuclear exportation of HDAC5 in the spinal GABAergic neurons may also provide potential targets in pain management.

In Chapter 5, we predicted and proved that the downregulated the spinal micro RNA 23a (miR23a) resulted in the over activation of C-X-C chemokine receptor 4 (CXCR4) and Thioredoxin-interacting protein (TXNIP), thus activated the NACHT, LRR and PYD domains-containing protein 3 (NLRP3 or NALP3) inflammasome in the spinal microglia, which medicated the nociception after nerve injury. And overexpressed the spinal miR-23a displayed the anti-nociceptive effects. This study reveals the epigenetic regulation role of over activating the spinal glial cells under neuropathic pain condition. Therefore, targeting of the miR-23a, spinal CXCR4 and TXNIP in the spinal glia cells also shows the potential in anti-nociception.

This thesis partly demonstrated the epigenetically regulation roles under neuropathic pain condition, and the signalling molecules involved may provide the potential therapeutic targets in pain management.