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

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.