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
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.