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Background

The existence of referred pain and ectopic paresthesia caused by tooth pulp inflammation may make definitive diagnosis difficult and cause misdiagnosis or mistreatment; thus, elucidation of that molecular mechanism is urgent. In the present study, we investigated the mechanisms underlying ectopic pain, especially tongue hyperalgesia, after tooth pulp inflammation.

Methods

A rat model with mandibular first molar tooth pulp exposure was employed. Tooth pulp exposure-induced heat and mechanical-evoked tongue hypersensitivity was measured, and immunohistochemical staining for Iba1, a marker of active macrophages, IL-1β, IL-1 type I receptor (IL-1RΙ), and toll-like receptor 4 in the trigeminal ganglion was performed. In addition, we investigated the effects of injections of liposomal clodronate Clophosome-A (LCCA), a selective macrophage depletion agent, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS, a toll-like receptor 4 antagonist), IL-1β, or heat shock protein 70 (Hsp70, a selective agonist of toll-like receptor 4), to examine changes in tongue hypersensitivity and in the regulation of IL-1RΙ, toll-like receptor 4, and transient receptor potential vanilloid 1 (TRPV1) biosynthesis.

Results

At day 1 after tooth pulp exposure, obvious tooth pulp inflammation was observed. Tooth pulp exposure-induced heat and mechanical tongue hypersensitivity was observed from days 1 to 3 after tooth pulp exposure. The production of IL-1β in activated macrophages and toll-like receptor 4 and IL-1RΙ expression were significantly increased in trigeminal ganglion neurons innervating the tongue following tooth pulp exposure. Intra-trigeminal ganglion injection of LCCA significantly suppressed tongue hypersensitivity; however, toll-like receptor 4 and IL-1RΙ expression in trigeminal ganglion neurons innervating the tongue was not significantly altered. Intra-trigeminal ganglion injection of LPS-RS significantly suppressed tongue hypersensitivity and reduced IL-1RΙ expression in the trigeminal ganglion neurons innervating the tongue following tooth pulp exposure. Intra-trigeminal ganglion injection of recombinant Hsp70 significantly promoted tongue hypersensitivity and increased IL-1RI expression in trigeminal ganglion neurons innervating the tongue in naive rats. Furthermore, intra-trigeminal ganglion injection of recombinant IL-1β led to tongue hypersensitivity and enhanced TRPV1 expression in trigeminal ganglion neurons innervating the tongue in naive rats.

Conclusions

The present findings suggest that the neuron-macrophage interaction mediated by toll-like receptor 4 and IL-1RI activation in trigeminal ganglion neurons affects the pathogenesis of abnormal tongue pain following tooth pulp inflammation via IL-1RI and TRPV1 signaling in the trigeminal ganglion. Further research may contribute to the establishment of new therapeutic and diagnostic methods."xsd:string
http://purl.uniprot.org/citations/33081813http://purl.org/dc/terms/identifier"doi:10.1186/s12974-020-01995-y"xsd:string
http://purl.uniprot.org/citations/33081813http://purl.uniprot.org/core/author"Hayashi M."xsd:string
http://purl.uniprot.org/citations/33081813http://purl.uniprot.org/core/author"Kanno K."xsd:string
http://purl.uniprot.org/citations/33081813http://purl.uniprot.org/core/author"Shimizu K."xsd:string
http://purl.uniprot.org/citations/33081813http://purl.uniprot.org/core/author"Iwata K."xsd:string
http://purl.uniprot.org/citations/33081813http://purl.uniprot.org/core/author"Shinoda M."xsd:string
http://purl.uniprot.org/citations/33081813http://purl.uniprot.org/core/author"Takeichi O."xsd:string
http://purl.uniprot.org/citations/33081813http://purl.uniprot.org/core/date"2020"xsd:gYear
http://purl.uniprot.org/citations/33081813http://purl.uniprot.org/core/name"J Neuroinflammation"xsd:string
http://purl.uniprot.org/citations/33081813http://purl.uniprot.org/core/pages"312"xsd:string
http://purl.uniprot.org/citations/33081813http://purl.uniprot.org/core/title"Role of macrophage-mediated Toll-like receptor 4-interleukin-1R signaling in ectopic tongue pain associated with tooth pulp inflammation."xsd:string
http://purl.uniprot.org/citations/33081813http://purl.uniprot.org/core/volume"17"xsd:string
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