Spinal CBX2 contributes to neuropathic pain by activating ERK signaling pathway in male mice

The deregulated spinal cord proteins induced by nerve injury are the key to neuropathic pain. Integrated transcriptome and translatome analyses can screen out deregulated proteins controlled by only post-transcriptional regulation. By comparing RNA sequencing (RNA-seq) and ribosome profiling sequencing (Ribo-seq) data, we identified an upregulated protein, chromobox 2 (CBX2), with its mRNA level unchanged in the spinal cord after peripheral nerve injury. CBX2 was mainly distributed in the spinal cord neurons. Blocking the SNL-induced increase of spinal CBX2 attenuated the neuronal and astrocytes hyperactivities and pain hypersensitivities in both the development and maintenance phases. Conversely, mimicking the upregulation of CBX2 in the spinal cord facilitated the activities of neurons and astrocytes and produced evoked nociceptive hypersensitivity and spontaneous pain. Our results also revealed that activating the ERK pathway, upregulating CXCL13 in neurons, and CXCL13 further inducing astrocyte activation were possible downstream signaling mechanisms of CBX2 in pain processing. In conclusion, upregulation of CBX2 after nerve injury leads to nociceptive hyperalgesia by promoting neuronal and astrocyte hyperactivities through the ERK pathway. Inhibiting CBX2 upregulation may be therapeutically beneficial.

Automated summary

Deregulated spinal cord proteins induced by nerve injury are crucial for neuropathic pain. Transcriptome and translatome analyses reveal that chromobox 2 (CBX2), an upregulated protein with unchanged mRNA level, plays a role in neuronal and astrocyte hyperactivities and pain hypersensitivities. The ERK pathway, CXCL13 upregulation in neurons, and further induction of astrocyte activation may be downstream signaling mechanisms of CBX2 in pain processing. Targeting CBX2 upregulation could be therapeutically beneficial.