Nat. Neurosci., published online 23 June 2013; doi:10.1038/nn.3438

The mechanisms underlying neuropathic pain include abnormal spontaneous activity in neurons of the dorsal root ganglion (DRG). Upon peripheral nerve injury, the expression of voltage-dependent potassium (Kv) channels is downregulated in the injured DRG neurons, which may help induce neuropathic pain. To understand the mechanism by which Kv channel downregulation contributes to development of pain, Zhao et al. asked whether long noncoding RNAs (lncRNAs), whose expression has recently been associated with disease, were at play. Searching a database of expressed sequence tags, the authors found one that represented the antisense sequence of the Kv1.2 channel transcript. This lncRNA was expressed in rat DRG neurons, with expressing neurons showing small amounts of Kv1.2 protein. Two types of nerve injury downregulated Kv1.2 mRNA and protein but upregulated the levels of lncRNA in the injured DRG neurons. This upregulation was attributed to nerve injury–induced increases in the expression of the transcriptional activator MZF1 and its binding to the promoter region of the lncRNA. Upregulating lncRNA downregulated Kv1.2 expression, reduced total Kv current and excitability in DRG neurons and produced neuropathic pain symptoms. Blocking nerve injury–induced increase in DRG lncRNA expression rescued nerve injury–evoked downregulation of DRG Kv1.2 and attenuated neuropathic pain. This discovery suggests that lncRNAs are potential targets in prevention and/or treatment of neuropathic pain.