Voltage‐gated potassium channels (Kv) are important regulators of neuronal excitability for its role of regulating resting membrane potential and repolarization. Recent studies show that Kv channels participate in neuropathic pain, but the detailed underlying mechanisms are far from being clear. In this study, we used siRNA, miR‐137 agomir, and antagomir to regulate the expression of Kv1.2 in spinal cord and dorsal root ganglia (DRG) of naïve and chronic constriction injury (CCI) rats. Kv currents and neuron excitability in DRG neurons were examined by patch‐clamp whole‐cell recording to verify the change in Kv1.2 function. The results showed that Kv1.2 was down‐regulated in DRG and spinal dorsal horn (SDH) by CCI. Knockdown of Kv1.2 by intrathecally injecting Kcna2 siRNA induced significant mechanical and thermal hypersensitivity in naïve rats. Concomitant with the down‐regulation of Kv1.2 was an increase in the expression of the miR‐137. The targeting and regulating of miR‐137 on Kcna2 was verified by dual‐luciferase reporter system and intrathecal injecting miR‐137 agomir. Furthermore, rescuing the expression of Kv1.2 in CCI rats, achieved through inhibiting miR‐137, restored the abnormal Kv currents and excitability in DRG neurons, and alleviated mechanical allodynia and thermal hyperalgesia. These results indicate that the miR‐137‐mediated Kv1.2 impairment is a crucial etiopathogenesis for the nerve injury‐induced neuropathic pain and can be a novel potential therapeutic target for neuropathic pain management.

Chronic postsurgical pain (CPSP) is a common complication after surgery; however, the underlying mechanisms of CPSP are poorly understood. As one of the most important inflammatory pathways, the Toll‐like receptor 4/nuclear factor‐kappa B (TLR4/NF‐κB) signaling pathway plays an important role in chronic pain. However, the precise role of the TLR4/NF‐κB signaling pathway in CPSP remains unclear. In the present study, we established a rat model of CPSP induced by skin/muscle incision and retraction (SMIR) and verified the effects and mechanisms of central and peripheral TLR4 and NF‐κB on hyperalgesia in SMIR rats. The results showed that TLR4 expression was increased in both the spinal dorsal horn and dorsal root ganglia (DRGs) of SMIR rats. However, the TLR4 expression pattern in the spinal cord was different from that in DRGs. In the spinal cord, TLR4 was expressed in both neurons and microglia, whereas it was expressed in neurons but not in satellite glial cells in DRGs. Further results demonstrate that the central and peripheral TLR4/NF‐κB signaling pathway is involved in the SMIR‐induced CPSP by different mechanisms. In the peripheral nervous system, we revealed that the TLR4/NF‐κB signaling pathway induced upregulation of voltage‐gated sodium channel 1.7 (Nav1.7) in DRGs, triggering peripheral hyperalgesia in SMIR‐induced CPSP. In the central nervous system, the TLR4/NF‐κB signaling pathway participated in SMIR‐induced CPSP by activating microglia in the spinal cord. Ultimately, our findings demonstrated that activation of the peripheral and central TLR4/NF‐κB signaling pathway involved in the development of SMIR‐induced CPSP.

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