Metabotropic glutamate receptor 5‐mediated inhibition of inward‐rectifying K⁺ channel 4.1 contributes to orofacial ectopic mechanical allodynia following inferior alveolar nerve transection in male mice

Abstract

Inward‐rectifying K+ channel 4.1 (Kir4.1), which regulates the electrophysiological properties of neurons and glia by affecting K+ homeostasis, plays a critical role in neuropathic pain. Metabotropic glutamate receptor 5 (mGluR5) regulates the expression of Kir4.1 in retinal Müller cells. However, the role of Kir4.1 and its expressional regulatory mechanisms underlying orofacial ectopic allodynia remain unclear. This study aimed to investigate the biological roles of Kir4.1 and mGluR5 in the trigeminal ganglion (TG) in orofacial ectopic mechanical allodynia and the role of mGluR5 in Kir4.1 regulation. An animal model of nerve injury was established via inferior alveolar nerve transection (IANX) in male C57BL/6J mice. Behavioral tests indicated that mechanical allodynia in the ipsilateral whisker pad lasted at least 14 days after IANX surgery and was alleviated by the overexpression of Kir4.1 in the TG, as well as intraganglionic injection of an mGluR5 antagonist (MPEP hydrochloride) or a protein kinase C (PKC) inhibitor (chelerythrine chloride); Conditional knockdown of the Kir4.1 gene downregulated mechanical thresholds in the whisker pad. Double immunostaining revealed that Kir4.1 and mGluR5 were co‐expressed in satellite glial cells in the TG. IANX downregulated Kir4.1 and upregulated mGluR5 and phosphorylated PKC (p‐PKC) in the TG; Inhibition of mGluR5 reversed the changes in Kir4.1 and p‐PKC that were induced by IANX; Inhibition of PKC activation reversed the downregulation of Kir4.1 expression caused by IANX (p < .05). In conclusion, activation of mGluR5 in the TG after IANX contributed to orofacial ectopic mechanical allodynia by suppressing Kir4.1 via the PKC signaling pathway.

Reduced circ_lrrc49 in trigeminal ganglion contributes to neuropathic pain in mice by downregulating Ist1 and impairing autophagy

“…As described in our previous studies (Li et al., 2023; Yang et al., 2022), orofacial mechanical hypersensitivity was evaluated by measuring the mechanical head withdrawal threshold (HWT) with Von Frey filaments (VFFs, Stoelting Company, Wood Dale, USA; cat. no.…”

“…Based on the previous studies of a similar nature (Feng et al., 2020; Li et al., 2023; Lin et al., 2022; Zhang et al., 2022), no formal sample size calculation was performed. The number of mice used for the study was determined based on the experience gained from these referenced studies.…”

“…In accordance with our previous studies (Li et al, 2023;Zhang et al, 2022), the administration of drugs into the TG was conducted with a stereotaxic apparatus. After anesthesia, the mice were secured onto the apparatus.…”

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

“…In our previous study, we discovered that trigeminal nerve injury leads to the down-regulation of Kir4.1 in the TG and that Kir4.1 knockdown in the TG is associated with orofacial mechanical allodynia (Li et al, 2023b). To further investigate the potential involvement of Kir4.1 in the regulation of Panx3 and its impact on orofacial neuropathic pain, we utilized male and female mice with conditional knockdown of Kir4.1 (Kcnj10 CKD) in the TG (Fig.…”

“…The development and persistence of orofacial neuropathic pain are attributed, in part, to peripheral sensitization of the trigeminal nervous system (Liu et al, 2022). In our previous research, we discovered a significant role of inwardly rectifying potassium channel 4.1 (Kir4.1) expressed specifically in trigeminal ganglion (TG) satellite glial cells (SGCs) in peripheral sensitization and the subsequent induction of orofacial neuropathic pain resulting from inferior alveolar nerve injury (Li et al, 2023a). However, the downstream signaling pathway through which Kir4.1 regulates the development of orofacial neuropathic pain remains poorly understood.…”