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Contribution of Inwardly Rectifying Potassium Channel 4.1 in Orofacial Neuropathic Pain: Regulation of Pannexin 3 via the Reactive Oxygen Species-Activated P38 MAPK Signal Pathway
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  • Yuheng Feng,
  • Renjie Tang,
  • Yanyan Zhang,
  • Jiu Lin,
  • Yajing Liu,
  • Yike Li,
  • Chunjie Li,
  • Cheng Zhou,
  • Fei Liu,
  • Jie-Fei Shen
Yuheng Feng
Sichuan University West China Hospital of Stomatology
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Renjie Tang
Sichuan University West China Hospital of Stomatology
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Yanyan Zhang
Sichuan University West China Hospital of Stomatology
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Jiu Lin
Sichuan University West China Hospital of Stomatology
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Yajing Liu
Sichuan University West China Hospital of Stomatology
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Yike Li
Sichuan University West China Hospital of Stomatology
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Chunjie Li
Sichuan University West China Hospital of Stomatology
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Cheng Zhou
Translational Neuroscience Center, West China Hospital of Sichuan University Tianfu Life Science Park
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Fei Liu
Sichuan University West China Hospital of Stomatology
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Jie-Fei Shen
Sichuan University West China Hospital of Stomatology

Corresponding Author:[email protected]

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Abstract

The involvement of inwardly rectifying potassium channel 4.1 (Kir4.1) in neuropathic pain has been established. However, there is limited understanding of the downstream mechanism through which Kir4.1 contributes to orofacial neuropathic pain. The objective of this study was to examine the regulation of Kir4.1 on the expression of pannexin 3 (Panx3) in the trigeminal ganglion (TG) and the underlying mechanism in the context of orofacial neuropathic pain caused by chronic constriction injury of the infraorbital nerve (CCI-ION). The study observed a significant increase in Panx3 expression in the TG of mice with CCI-ION. Inhibition of Panx3 in the TG of CCI-ION mice resulted in alleviation of orofacial mechanical allodynia. Furthermore, conditional knockdown (CKD) of Kir4.1 in the TG of both male and female mice led to mechanical allodynia and up-regulation of Panx3 expression. Conversely, overexpression of Kir4.1 decreased Panx3 levels in the TG and relieved mechanical allodynia in CCI-ION mice. In addition, silencing Kir4.1 in satellite glial cells (SGCs) decreased Panx3 expression and increased the phosphorylation of P38 MAPK. Moreover, silencing Kir4.1 in SGCs increased the levels of reactive oxygen species (ROS). The elevated phosphorylation of P38 MAPK resulting from Kir4.1 silencing was inhibited by using a superoxide scavenger known as the tempol. Silencing Panx3 in the TG in vivo attenuated the mechanical allodynia caused by Kir4.1 CKD. In conclusion, these findings suggest that the reduction of Kir4.1 promotes the expression of Panx3 by activating the ROS-P38 MAPK signaling pathway, thus contributing to the development of orofacial neuropathic pain.
01 Aug 2023Submitted to European Journal of Neuroscience
04 Aug 2023Assigned to Editor
04 Aug 2023Submission Checks Completed
04 Aug 2023Review(s) Completed, Editorial Evaluation Pending
08 Aug 2023Reviewer(s) Assigned
23 Oct 2023Editorial Decision: Revise Major