Inhibition of MicroRNA-221 Alleviates Neuropathic Pain Through Targeting Suppressor of Cytokine Signaling 1

Abstract

Neuropathic pain results in considerable trouble to people's physical and mental health. The pathophysiological mechanisms underlying its occurrence and development remain unclear. A large number of experiments show that microRNAs (miRNAs) play a major role in the pathogenesis of neuropathic pain and neuroinflammation resulting from nerve injury. Among various miRNAs, microRNA-221 (miR-221) overexpression has been reported in a chronic constrictive injury (CCI)-induced rat model of neuropathic pain. However, the role of miR-221 in the regulation of neuropathic pain is unknown. In this study, we investigated the potential role and underlying mechanism of miR-221 in regulating neuropathic pain. Our findings show that miR-221 is overexpressed in the spinal cord and the isolated microglia of CCI rats. Intrathecal injection of a miR-221 inhibitor attenuated CCI-induced mechanical allodynia and thermal hyperalgesia, and reduced proinflammatory cytokine expression, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in CCI rats. Using a dual-luciferase reporter assay, we show that suppressor of cytokine signaling 1 (SOCS1), an important regulator of inflammation, is a direct target of miR-221. Treatment with the miR-221 inhibitor significantly inhibited the expression of SOCS1. Furthermore, the miR-221 inhibitor markedly suppressed the activation of nuclear factor-kappa B (NF-κB) and the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. Knockdown of SOCS1 in CCI rats abrogated the inhibitory effect of the miR-221 inhibitor on CCI-induced neuropathic pain and the NF-κB and p38 MAPK signaling pathways. Together, these results suggest that inhibition of miR-221 alleviates neuropathic pain and neuroinflammation through increasing SOCS1 and by inhibiting the NF-κB and p38 MAPK signaling pathways, indicating that miR-221 may be a promising molecular target for the treatment of neuropathic pain.

Differential expression profiles of circulating microRNAs in newborns associated to maternal pregestational overweight and obesity

“…miR‐146a is considered an important part of feedback mechanisms in response to inflammatory stimuli, modulating inflammatory responses through IRAK‐1 and other targets . Recently, the role of miR‐221 in inflammation, through targeting of SOCS1 and modulation of the NF‐kB and p38 MAPK signalling pathways, has been suggested . In our study, miR‐146a and miR‐221 expression correlated with IL‐1b in newborns from normal weight mothers (Fig.…”

MiR‐150 alleviates neuropathic pain via inhibiting toll‐like receptor 5

“…40 Inhibition of MicroRNA-221 alleviates neuropathic pain through targeting suppressor of cytokine signaling 1. 41 By regulating suppressor of cytokine signaling 3, Downregulation of microRNA-218 can relieve neuropathic pain. 32 These studies have indicated that targeting specific miRNAs can reduce neuropathic pain development.…”

MicroRNA-142-3p relieves neuropathic pain by targeting high mobility group box 1

“…A study by Shi et al (39) reported that miR-195 induced by SNL aggravated neuropathic pain by inhibiting Atg14. Suppression of miR-155, miR-19a or miR-221 inhibited neuropathic pain through targeting suppressor of cytokine signaling 1 (11,40,41). Intrathecal injection of miR-96 and miR-183 alleviated neuropathic pain by downregulation of sodium channel Nav1.3 expression (42,43).…”