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

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.

In vivo calcium imaging identifies functionally and molecularly distinct subsets of tongue-innervating mechanosensory neurons

“…In addition, due to the relatively small sample size that is feasible to achieve with microneurography, these rare units may not have been captured. One previous study recorded pressure-response dynamics in tongue-innervating mechanosensory neurons using mouse tongue-nerve preparations (Grayson et al, 2019). This study found that high-threshold mechanoreceptors were the most abundant class present in the tongue.…”

“…The anatomy of these mechanosensory terminals are distinct from Piezo2-positive afferents in skin and other tissues; therefore, their functions in sensation are unknown. Previous electrophysiological studies identified a variety of physiological types of neurons innervating the tongues humans, cats and mice (Biedenbach & Chan, 1971; Grayson et al, 2019; Robinson, 1992; Smith & Robinson, 1995; Trulsson & Essick, 1997, 2010). In humans and cats, the majority of tongue mechanoreceptors are rapidly adapting, a typical property of Meissner corpuscles, indicating that the tongue is tuned for the detection of moving stimuli (Biedenbach & Chan, 1971; Mountcastle et al, 1967; Robinson, 1992; Trulsson & Essick, 1997, 2010).…”

Acute and Chronic Pain from Facial Skin and Oral Mucosa: Unique Neurobiology and Challenging Treatment

“…Aδ polymodal nociceptors are rare in the skin but enriched in visceral afferents [ 21 ]. A recent study has also shown the characteristics of afferents innervated to the tongue in mice [ 22 ]. Approximately 50% of lingual afferents are c fibers, while approximately 30% are Aδ fibers.…”

“…Approximately 50% of lingual afferents are c fibers, while approximately 30% are Aδ fibers. In this study, the implantation of oral squamous carcinoma into the tongue increased spontaneous firing, decreased the mechanical thresholds of the c and Aδ mechanoreceptors, and reduced the proportion of mechanically insensitive fibers [ 22 ].…”

“…Multiple factors, such as endothelin, nerve growth factor (NGF), adenosine triphosphate, proton, and proteases, are released from cancer cells and attract immune cells to eventually induce the peripheral sensitization of nociceptive afferents [ 50 ]. The inoculation of SCC cells into the tongue leads to peripheral sensitization [ 22 ] and central sensitization in Vc [ 51 ]. More studies are warranted, in order to obtain a detailed understanding of the unique peripheral and central molecular mechanisms of oral cancer pain.…”