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.
Highlights
Chronic pain constitutes an enormous ongoing health problem, yet, despite centuries of research and investment, the new treatments are slow coming and opioids are still a “gold standard.” Pathological changes within both peripheral and central nociceptive pathways contribute to the development and maintenance of chronic pain.[10]
No specific antibody binding was detected in dorsal root ganglion (DRG) of mice injected with saline or an empty AAV2/9, whereas multiple DRG cell bodies from the AAV2/9-repressor element 1–silencing transcription factor (REST)–injected animals displayed fluorescent staining indicative of the exogenous expression of the Myc-tagged REST (Fig. 1C)
We demonstrated that transcriptional suppressor REST is necessary and sufficient for the development of hyperalgesic state after chronic nerve injury or inflammation
Summary
Chronic pain constitutes an enormous ongoing health problem, yet, despite centuries of research and investment, the new treatments are slow coming and opioids are still a “gold standard.” Pathological changes within both peripheral and central nociceptive pathways contribute to the development and maintenance of chronic pain.[10]. Chronic pain constitutes an enormous ongoing health problem, yet, despite centuries of research and investment, the new treatments are slow coming and opioids are still a “gold standard.”. Pathological changes within both peripheral and central nociceptive pathways contribute to the development and maintenance of chronic pain.[10] One of the common peripheral causes of chronic pain is a pathological activity of a subset of peripheral nerves (nociceptors), which are normally silent and only become active in response to potentially damaging noxious stimuli. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
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