Sympathetic Modulation of Oral Cancer Pain via Adrenergic Signaling in Trigeminal Primary Afferent Neurons

Abstract

Head and neck squamous cell carcinoma (HNSCC) often codevelops with severe functional pain that significantly impacts patients' quality of life. Previous research demonstrated dense innervation of sympathetic and sensory nerves within the oral tumor microenvironment. We hypothesize that nociceptive afferents innervating oral cancer develop adrenergic sensitivity resulting in sympathetically maintained pain. Patient-reported pain in tandem with patient blood and tumor samples were used to explore the relationship between tumor-innervating sympathetic nerves and cancer pain. A syngeneic tongue transplant mouse oral cancer (MOC2) model and an orofacial behavioral assay using gnaw-time as an index of pain were used to quantify cancer-induced nociceptive behavior. qPCR was performed on trigeminal ganglia (TGs) from MOC2-tumor-bearing mice to investigate the effect of oral cancer on adrenergic receptor gene expression. Sympathetic nerve fibers, identified using tyrosine hydroxylase (TH) immunoreactivity, comprised 4.73± 1.3% of total nerve area across 13 HNSCC tumor samples. We found a positive correlation (r2=0.309) between TH nerve presence and patient-reported pain using the FACT-H&N questionnaire. Furthermore, we quantified a 2-fold increase in platelet NE concentration isolated from HSNCC patient plasma compared to healthy controls and there was a positive correlation (r2=0.687) between NE concentration and patient reported pain. MOC2 tumor progression evoked orofacial nociceptive behavior in female mice; there was a 198.8±20.5% and 478.5±146.8% increase in gnaw-time at post inoculation day (PID) 7 and 14 respectively compared to sham mice. PID14 was also associated with significant changes in adrenergic gene expression in TG from tumor-bearing female compared to control mice; there was a 2-fold increase in genes for the following adrenergic receptor subtypes: Adra1b, Adra2b, and Adrb2. Future investigation using adrenergic blockade will further support the role of sympathetic modulation of oral cancer pain and allow for better and more focused treatment options for these patients. Grant support from NIH NIDCR R01DE030892.