Nav1.7 via Promotion of ERK in the Trigeminal Ganglion Plays an Important Role in the Induction of Pulpitis Inflammatory Pain

Abstract

The trigeminal ganglion (TG) refers to sensory neurons bodies that innervate the spinal cord and peripheral axons that innervate teeth. The tetrodotoxin-sensitive sodium (NA) channels (Nav1.7) play important roles in the pathophysiology of pain. In this study, we investigated the TG expression of Nav1.7 and extracellular signal-regulated kinase (ERK) in a rat model of pulpitis to explore the correlation between these channels and inflammatory pain. Pulpitis was confirmed by hematoxylin-eosin staining. In this study, we demonstrated that the reflex of rats to mechanical stimulation increases after pulp exposure and that the exposed rat molar pulp can upregulate the expression of Nav1.7 and ERK in the rat TG. Three days after rat pulp exposure, the expression levels of the two ion channels in the TG increased. TG target injection of PF04856264, a Nav1.7 inhibitor, dose-dependently increased the mechanical pain threshold and was able to inhibit ERK expression. TG target injection of PD98059, an ERK inhibitor, dose-dependently increased the mechanical pain threshold. These factors simultaneously resulted in the highest production. In this study, with the established link to inflammatory pain, we found that Nav1.7 and ERK both play important roles in the induction of inflammatory pain caused by pulpitis. We also found a correlation between the expression levels of Nav1.7 and ERK and the degree of inflammatory pain. Furthermore, ERK signaling pathways were promoted by the Nav1.7 in TG after pulpitis.

Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia

“…Among them, one ∼500-kb duplication covering the serine-threonine kinase MAPK3 was shared by the proband and the affected mother, but not the unaffected father in family TRGN190. MAPK3 has been previously implicated in the pathogenesis of multiple trigeminal pain models ( Alter et al., 2010 ; Liverman et al., 2009 ; Smyth et al., 2003 ; Sun et al., 2019 ). Interestingly, the TRGN190 proband with the MAPK3 duplication was diagnosed with bilateral cTN-1 at 11 years of age and exhibited bilateral NVC on brain magnetic resonance imaging (MRI).…”

The Genetic and Epigenetic Mechanisms Involved in Irreversible Pulp Neural Inflammation

“…Looking at the case of MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1), this gene encodes a serine/threonine kinase and has been shown to be part of many signaling transduction cascades including ERK (extracellular signal-regulated kinases) [30] and JNK (c-Jun N-terminal kinase) kinase [31], NF-kappa B [32], TLR4 signaling [33], and IL-1 family signaling pathways [32]. Since these pathways mentioned here have been verified to be implicated in pulpitis [34][35][36], MAP3K1 can be speculated to be also involved in pulpal inflammation. Taking the case of HIF1A (hypoxia-inducible factor 1 subunit alpha), this gene encodes the alpha subunit of transcription factor hypoxia-inducible factor-1 (HIF-1) [37].…”

Inhibition of the Nav1.7 Channel in the Trigeminal Ganglion Relieves Pulpitis Inflammatory Pain

“…Most subtypes that have been included in this pain pathway are Nav1.7, Nav1.8, and Nav1.9 ( Fang et al, 2002 ; Luo et al, 2010 ). Among these channel subtypes, the expression of Nav1.7 increased in various chronic pain states ( Dib-Hajj et al, 2007 ; Sun et al, 2019 ). Consistent with the results of previous studies, our investigation also confirmed that the expression level of Nav1.7 in TGs was upregulated in the pulpitis state.…”

“…Alterations in primary afferent nerve fibers result in increased excitability, which causes hyperalgesia ( Byers and Närhi, 1999 ). These functional changes may be manipulated by specific signaling components in neurons ( Sun et al, 2019 ). Ectopic neuronal activity triggered by increasing sensitization is coincident with changes in the expressions of several ion channels and receptors ( Julius and Basbaum, 2001 ; Davies et al, 2006 ).…”

“…Many studies have shown that VGSCs control nerve excitability, inclusive of action potentials ( Padilla et al, 2007 ; Luo et al, 2010 ). Moreover, they play an essential role in the conduction of electrical excitability ( Rogers et al, 2006 ; Bi et al, 2016 ; Liu et al, 2019 ; Sun et al, 2019 ). Previous studies have indicated that sensory neurons alter the expression of VGSCs after inflammatory lesions ( Wood et al, 2004 ; Dib-Hajj et al, 2010 ).…”