Nerve Injury-Induced γH2AX Reduction in Primary Sensory Neurons Is Involved in Neuropathic Pain Processing

Phosphorylation of the serine 139 of the histone variant H2AX (?H2AX) is a DNA damage marker that regulates DNA damage response and various diseases. However, whether ?H2AX is involved in neuropathic pain is still unclear. We found the expression of ?H2AX and H2AX decreased in mice dorsal root ganglion (DRG) after spared nerve injury (SNI). Ataxia telangiectasia mutated (ATM), which promotes ?H2AX, was also down-regulated in DRG after peripheral nerve injury. ATM inhibitor KU55933 decreased the level of ?H2AX in ND7/23 cells. The intrathecal injection of KU55933 down-regulated DRG ?H2AX expression and significantly induced mechanical allodynia and thermal hyperalgesia in a dose-dependent manner. The inhibition of ATM by siRNA could also decrease the pain threshold. The inhibition of dephosphorylation of ?H2AX by protein phosphatase 2A (PP2A) siRNA partially suppressed the down-regulation of ?H2AX after SNI and relieved pain behavior. Further exploration of the mechanism revealed that inhibiting ATM by KU55933 up-regulated extracellular-signal regulated kinase (ERK) phosphorylation and down-regulated potassium ion channel genes, such as potassium voltage-gated channel subfamily Q member 2 (Kcnq2) and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in vivo, and KU559333 enhanced sensory neuron excitability in vitro. These preliminary findings imply that the down-regulation of ?H2AX may contribute to neuropathic pain.

Automated summary

In neuropathic pain, the expression of ?H2AX and ATM is downregulated. Inhibiting ATM with KU55933 can reduce the level of ?H2AX and induce mechanical allodynia and thermal hyperalgesia. Further studies show that inhibiting ATM can upregulate ERK phosphorylation and downregulate potassium ion channel genes, increasing sensory neuron excitability.