Abstract
miR-17-92 is a microRNA cluster with six distinct members. Here, we show that the miR-17-92 cluster and its individual members modulate chronic neuropathic pain. All cluster members are persistently upregulated in primary sensory neurons after nerve injury. Overexpression of miR-18a, miR-19a, miR-19b and miR-92a cluster members elicits mechanical allodynia in rats, while their blockade alleviates mechanical allodynia in a rat model of neuropathic pain. Plausible targets for the miR-17-92 cluster include genes encoding numerous voltage-gated potassium channels and their modulatory subunits. Single-cell analysis reveals extensive co-expression of miR-17-92 cluster and its predicted targets in primary sensory neurons. miR-17-92 downregulates the expression of potassium channels, and reduced outward potassium currents, in particular A-type currents. Combined application of potassium channel modulators synergistically alleviates mechanical allodynia induced by nerve injury or miR-17-92 overexpression. miR-17-92 cluster appears to cooperatively regulate the function of multiple voltage-gated potassium channel subunits, perpetuating mechanical allodynia.
Highlights
MiR-17-92 is a microRNA cluster with six distinct members
Using quantitative PCR, we first confirmed that expression of each miR-17-92 cluster member (Supplementary Fig. 1a) was significantly upregulated in the dorsal root ganglion (DRG) 14 days after ligation of the fifth lumbar (L5) nerve, as observed in our previous microarray analysis[6] (Fig. 1a)
Upregulation was sustained from day 1 to day 28 after L5 spinal nerve ligation (SNL; Fig. 1a); neuropathic pain was evident at the same time (Fig. 1b)
Summary
MiR-17-92 is a microRNA cluster with six distinct members. Here, we show that the miR-1792 cluster and its individual members modulate chronic neuropathic pain. Many voltage-gated potassium channel a subunits were among the plausible target genes downregulated following nerve injury and predicted as targets of pain-relevant miR-17-92 cluster members (Fig. 4a), including KV1.1, KV1.4 and KV4.3 (refs 21–25). Microarray analysis revealed that injection of an AAV vector encoding the whole miR-17-92 cluster decreased the expression of all voltage-gated potassium channel subunits targeted by miR-17-92 (n 1⁄4 4; Supplementary Table 1).
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