RT Journal Article
SR Electronic
T1 The transcription factor C/EBPβ in the dorsal root ganglion contributes to peripheral nerve trauma–induced nociceptive hypersensitivity
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP eaam5345
DO 10.1126/scisignal.aam5345
VO 10
IS 487
A1 Li, Zhisong
A1 Mao, Yuanyuan
A1 Liang, Lingli
A1 Wu, Shaogen
A1 Yuan, Jingjing
A1 Mo, Kai
A1 Cai, Weihua
A1 Mao, Qingxiang
A1 Cao, Jing
A1 Bekker, Alex
A1 Zhang, Wei
A1 Tao, Yuan-Xiang
YR 2017
UL http://stke.sciencemag.org/content/10/487/eaam5345.abstract
AB Neuropathic pain is a chronic type of pain that develops after injury to peripheral nerves. It is associated with reduced responses to morphine-related analgesics and decreased abundance of Kv1.2, a voltage-gated potassium channel, and the μ opioid receptor (MOR) due to epigenetic silencing of the genes encoding these proteins in the dorsal root ganglion, a cluster of sensory neurons involved in pain transmission. Li et al. found that the transcription factor C/EBPβ activated the gene encoding the epigenetic silencer in a mouse model of peripheral nerve injury. Silencing C/EBPβ in the dorsal root ganglia decreased pain hypersensitivity and improved morphine analgesia after peripheral nerve injury. In contrast, overexpression of C/EBPβ in the dorsal root ganglia resulted in hypersensitivity to various painful stimuli in the absence of nerve injury. Thus, targeting C/EBPβ may prevent the gene expression changes that lead to the development of neuropathic pain after peripheral nerve injury.Changes in gene transcription in the dorsal root ganglion (DRG) after nerve trauma contribute to the genesis of neuropathic pain. We report that peripheral nerve trauma caused by chronic constriction injury (CCI) increased the abundance of the transcription factor C/EBPβ (CCAAT/enhancer binding protein β) in the DRG. Blocking this increase mitigated the development and maintenance of CCI-induced mechanical, thermal, and cold pain hypersensitivities without affecting basal responses to acute pain and locomotor activity. Conversely, mimicking this increase produced hypersensitivity to mechanical, thermal, or cold pain. In the ipsilateral DRG, C/EBPβ promoted a decrease in the abundance of the voltage-gated potassium channel subunit Kv1.2 and μ opioid receptor (MOR) at the mRNA and protein levels, which would be predicted to increase excitability in the ipsilateral DRG neurons and reduce the efficacy of morphine analgesia. These effects required C/EPBβ-mediated transcriptional activation of Ehmt2 (euchromatic histone-lysine N-methyltransferase 2), which encodes G9a, an epigenetic silencer of the genes encoding Kv1.2 and MOR. Blocking the increase in C/EBPβ in the DRG improved morphine analgesia after CCI. These results suggest that C/EBPβ is an endogenous initiator of neuropathic pain and could be a potential target for the prevention and treatment of this disorder.