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Repressor element 1-silencing transcription factor drives the development of chronic pain states.


ABSTRACT: Chronic pain is an unmet clinical problem with vast individual, societal, and economic impact. Pathologic activity of the peripheral somatosensory afferents is one of the major drivers of chronic pain. This overexcitable state of somatosensory neurons is, in part, produced by the dysregulation of genes controlling neuronal excitability. Despite intense research, a unifying theory behind neuropathic remodelling is lacking. Here, we show that transcriptional suppressor, repressor element 1-silencing transcription factor (REST; neuron-restrictive silencing factor, NRSF), is necessary and sufficient for the development of hyperalgesic state after chronic nerve injury or inflammation. Viral overexpression of REST in mouse dorsal root ganglion (DRG) induced prominent mechanical and thermal hyperalgesia in vivo. Sensory neuron-specific, inducible Rest knockout prevented the development of such hyperalgesic state in 3 different chronic pain models. Genetic deletion of Rest reverted injury-induced hyperalgesia. Moreover, viral overexpression of REST in the same neurons in which its gene has been genetically deleted restored neuropathic hyperalgesia. Finally, sensory neuron specific Rest knockout prevented injury-induced downregulation of REST target genes in DRG neurons. This work identified REST as a major regulator of peripheral somatosensory neuron remodelling leading to chronic pain. The findings might help to develop a novel therapeutic approache to combat chronic pain.

SUBMITTER: Zhang F 

PROVIDER: S-EPMC6756259 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Repressor element 1-silencing transcription factor drives the development of chronic pain states.

Zhang Fan F   Gigout Sylvain S   Liu Yu Y   Wang Yiying Y   Hao Han H   Buckley Noel J NJ   Zhang Hailin H   Wood Ian C IC   Gamper Nikita N  

Pain 20191001 10


Chronic pain is an unmet clinical problem with vast individual, societal, and economic impact. Pathologic activity of the peripheral somatosensory afferents is one of the major drivers of chronic pain. This overexcitable state of somatosensory neurons is, in part, produced by the dysregulation of genes controlling neuronal excitability. Despite intense research, a unifying theory behind neuropathic remodelling is lacking. Here, we show that transcriptional suppressor, repressor element 1-silenci  ...[more]

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