The nature of trigeminal neuropathic pain (TN) attacks is regarded as the ignition of ectopic action potentials from the trigeminal root following vascular compression, which seemed to be related to transmembrane proteins and inflammation factors. This study focused on the mechanosensitive channel Piezo2 and cytokine IL-6.

Background: It is necessary to understand the mechanism of trigeminal neuralgia (TN) and hemifacial spasm (HFS) in order to seek for an effective noninvasive remedy. As previous studies implied that inflammatory cytokines induced by demyelination following the nerve injury may be the initiated factor causing neuropathic pain, we attempt to analyze the correlation between cytokines and these hyperactive cranial nerve disorders. Method: The consecutive patients whose diagnosis were confirmed by microvascular decompression surgery as primary TN or HFS caused by vascular compression and healthy volunteers between March and May 2018 in XinHua Hospital Shanghai JiaoTong University School of Medicine were recruited. Preoperatively, venous blood was collected and the protein concentrations of IL-1β, IL-2, IL-6, IL-8, IL-10, TNF-α and IFN-γ were determined with ELISA. Each cytokine was compared between the patients and healthy volunteers. Results: Ultimately, 28 healthy volunteers as well as 44 TN and 47 HFS patients were enrolled in this investigation. The serum levels of IL-1β, IL-6, IL-8 and TNF-α in either HFS or TN patients were significantly higher than that in healthy volunteers (p < 0.05), yet which were similar between TN and HFS patients (p > 0.05). Besides, there was a significantly correlation between IL-6 concentration and severity of HFS (r = 0.933, p < 0.05) or TN (r = 0.943, p < 0.05). Discussion: Vascular compression of trigeminal or facial nerve roots may induce a rise in variety of cytokines, and IL-6 may play an important role in the signaling pathways to generate ectopic impulses from these cranial nerves.

Despite the etiology of trigeminal neuralgia has been verified by microvascular decompression as vascular compression of the trigeminal root, very few researches concerning its underlying pathogenesis has been reported in the literature. The present study focused on those voltage-gated sodium channels, which are the structural basis for generation of ectopic action potentials. The trigeminal neuralgia modeling was obtained with infraorbital nerve chronic constriction injury (ION-CCI) in rats. Two weeks postoperatively, the infraorbital nerve (TN), the trigeminal ganglion (TG) and the brain stem (BS) were removed and analyzed with a series of molecular biological techniques. Western blot depicted a significant up-regulation of Nav1.3 in TN and TG but not in BS, while none of the other isoforms (Nav1.6, Nav1.7, Nav1.8 or Nav1.9) presented a statistical change. The Nav1.3 from ION-CCI group was quantified as 2.5-fold and 1.7-fold than that from sham group in TN and TG, respectively (p < 0.05). Immunocytochemistry showed the Nav1.3-IR from ION-CCI group accounted for 21.2 ± 2.3% versus 6.1 ± 1.2% from sham group in TN, while the Nav1.3-positive neurons from ION-CCI group accounted for 34.1 ± 3.5% versus 11.2 ± 1.8% from sham group in TG. Immunohistochemical labeling showed the Nav1.3 was co-localized with CGRP and IB4 but not with GFAP or NF-200 in TG. ION-CCI may give rise to an up-regulation of Nav1.3 in trigeminal nerve as well as in C-type neurons at the trigeminal ganglion. It implied that the ectopic action potential may generate from both the compressed site of the trigeminal nerve and the ganglion rather than from the trigeminal nuclei.

Background: To verify the hypothesis that the nature of trigeminal neuralgia (TN) is an ectopic impulse induced by sodium channel modulated by cytokines, we conducted an animal study using the infraorbital nerve chronic constriction injury (CCI) model in rats. Method: The expression of Nav1.3 or IL-6 in the infraorbital nerve (ION) and trigeminal ganglion (TG) were detected by western blot and immunocytochemistry after administration of antisense oligodeoxynucleotide sequence (AS), IL-6 or Anti-IL-6. Results: With intrathecal administration of AS or mismatch oligodeoxynucleotide sequence (MM) in the CCI rats, the Nav1.3-IR in ION and TG accounted for 2.2 ± 0.51% and 8.5 ± 3.1% in AS+CCI group vs. 6.9 ± 1.3% and 38.7 ± 4.8% in MM+CCI group (p < 0.05), respectively. While with local administration of IL-6 in those with sham operation, it accounted for 7.4 ± 2.1% and 45.5 ± 3.4% in IL-6+ sham group vs. 1.9 ± 0.67% and 8.1 ± 1.3% in vehicle+sham group (p < 0.05); with local administration of anti-IL-6 in CCI rats, 4.5 ± 0.78% and 32.1 ± 9.6% in Anti-IL-6+ CCI group vs 8.9 ± 2.1% and 61.4 ± 11.2% in vehicle+CCI group (p < 0.05). Discussion: We believe that the emergence of Na_v1.3 from the compressed trigeminal nerve might be an important structural basis for the development of the ectopic excitability on the axon and IL-6 may play a role of necessary precondition.