A sensory neuron-specific long non-coding RNA reduces neuropathic pain by rescuing KCNN1 expression

Wang et al. identify a sensory neuron-specific long non-coding RNA expressed predominantly in small neurons of the dorsal root ganglion, and show that this RNA contributes to the development and maintenance of neuropathic pain by regulating KCNN1 expression. Nerve injury to peripheral somatosensory system causes refractory neuropathic pain. Maladaptive changes of gene expression in primary sensory neurons are considered molecular basis of this disorder. Long non-coding RNAs (lncRNAs) are key regulators of gene transcription; however, their significance in neuropathic pain remains largely elusive.Here, we reported a novel lncRNA, named sensory neuron-specific lncRNA (SS-lncRNA), for its expression exclusively in dorsal root ganglion (DRG) and trigeminal ganglion. SS-lncRNA was predominantly expressed in small DRG neurons and significantly downregulated due to a reduction of early B cell transcription factor 1 in injured DRG after nerve injury. Rescuing this downregulation reversed a decrease of the calcium-activated potassium channel subfamily N member 1 (KCNN1) in injured DRG and alleviated nerve injury-induced nociceptive hypersensitivity. Conversely, DRG downregulation of SS-lncRNA reduced the expression of KCNN1, decreased total potassium currents and afterhyperpolarization currents and increased excitability in DRG neurons and produced neuropathic pain symptoms.Mechanistically, downregulated SS-lncRNA resulted in the reductions of its binding to Kcnn1 promoter and heterogeneous nuclear ribonucleoprotein M (hnRNPM), consequent recruitment of less hnRNPM to the Kcnn1 promoter and silence of Kcnn1 gene transcription in injured DRG.These findings indicate that SS-lncRNA may relieve neuropathic pain through hnRNPM-mediated KCNN1 rescue in injured DRG and offer a novel therapeutic strategy specific for this disorder.

Automated summary

This study identifies a sensory neuron-specific long non-coding RNA, SS-lncRNA, which is predominantly expressed in small neurons of the dorsal root ganglion and contributes to the development and maintenance of neuropathic pain by regulating KCNN1 expression. The downregulation of SS-lncRNA leads to a decrease in KCNN1 expression and the development of neuropathic pain symptoms.