Depiction of Oral Tumor-Induced Trigeminal Afferent Responses Using Single-Fiber Electrophysiology

Max Grayson,Ashley Furr,Shivani Ruparel

doi:10.1038/s41598-019-39824-9

Abstract

Considerable gap in knowledge exists about the mechanisms by which oral tumors regulate peripheral sensory fibers to produce pain and altered sensations. To address this gap, we used a murine model of oral squamous cell carcinoma (OSCC) of the tongue to investigate changes in response properties of trigeminal afferent neurons. Using this model, we developed an ex vivo method for single neuron recordings of the lingual nerve from isolated tongue tissue. Our data demonstrated that the tongue tumor produced increased spontaneous firing of lingual fibers compared to control as well as produced mechanical hypersensitivity and reduced von Frey thresholds of C- and A-slow-high-threshold mechanoreceptors (HTMR) fibers but had no effect on C-LTMR, A-slow-LTMR and A-fast lingual fibers. Mechanically-insensitive fibers were also detected in lingual afferents of the control group, that were significantly decreased in tumor-bearing preparations. Collectively, using single fiber electrophysiology of lingual sensory fibers, we show that human OSCC tumors sensitize peripheral trigeminal nerve terminals, providing a unique opportunity to study mechanisms of oral cancer pain.

Highlights

Data are analyzed with one-way ANOVA with Bonferroni post hoc test at p < 0.05. n = 13 fibers in normal group and n = 17 fibers in tumor group. (b) von Frey Thresholds of A-slow -high-threshold mechanoreceptors (HTMR) fibers from normal and tumor group
Data are analyzed with one-way ANOVA with Bonferroni post hoc test at p < 0.05. n = 13 fibers in normal group and n = 17 fibers in tumor group. (b) von Frey Thresholds of C-LTMR fibers from normal and tumor group
Data are analyzed with Mann Whitney U test at p < 0.05. (c) Conduction velocity of C-LTMR fibers from normal and tumor group

Summary

Introduction

(d,e) Representative traces for normal and tumor groups showing A- slow-HTMR fiber responses upon sustained mechanical forces. We recorded a total of another 93 fibers from normal tongue-nerve preparations and 135 fibers from tumor bearing preparation to evaluate spontaneous activity and mechanical responses in both groups. The current study employed a previously reported orthotopic tongue cancer pain model in mice[20], that mimics patient reported symptoms with an ex vivo single-fiber recording method to www.nature.com/scientificreports

Results

Conclusion