Sensory-Sympathetic Nerve Interplay in Oral Cancer - Project Summary The majority of patients with head and neck squamous cell carcinoma (HNSCC) present with severe pain, which exceeds the levels seen in other cancers. Due to a multitude of factors, including the amplification of standard therapies, HNSCC patients are now living longer with the effects of their cancer and its treatment. The presence of pretreatment pain has been identified as a prognostic indicator of poor survival. In the presence of nerve injury and neuropathic pain, it has been demonstrated that adrenergic plasticity, as well as sympathetic sprouting, occur, leading to sympathetic-sensory coupled pain. We have previously demonstrated that aggressive tongue tumor growth drives nerve injury in tongue-innervating trigeminal ganglia neurons. Using an oral cancer mouse model, I discovered sensory neuron hypersensitivity to NE or “adrenergic sensitivity” in tongue-innervating trigeminal ganglia (TG) afferents using calcium imaging. While under basal conditions sensory neurons are unaffected, NE (10µM) evoked a Ca2+ transient in 91.2% of tongue innervating trigeminal ganglia neurons (TGNs) from tumor-bearing mice compared to 9% from sham. These data suggest adrenergic neurotransmission sensitizes nociceptive (i.e. pain sensing) sensory neuron during oral tumorigenesis. NE-induced calcium response suggests a role for sympathetic-induced depolarization to exacerbate oral cancer pain; however, the impact of alpha-adrenergic activity on nociceptive behavior in tumor- bearing animals in vivo has not yet been evaluated, and the exact mechanisms that underlie the development of adrenergic sensitivity in the TG has yet to be elucidated. The hypothesis of this proposal is that sympathetic neurotransmission secondary to oral cancer-induced nerve injury drives spontaneous/ongoing pain via adrenergic sensitivity in tongue-innervating nociceptive neurons. To test this hypothesis, I will use a syngeneic orthotopic oral cancer mouse model to assess the contribution of sympathetic post-ganglionic input to evoked and spontaneous orofacial pain behavior. I will also determine if sympathetic postganglionic input is required for the induction of sensory adrenergic plasticity in the presence of oral cancer. Clinically, I will begin to characterize spontaneous/ongoing pain and sympathetic innervation in a patient population using established neuropathic pain questionnaires as well as collect blood and tissue samples to assess circulating NE and intertumoral sympathetic nerve density. The successful completion of the proposed experiments and training program will further my knowledge of the relationship between sensory and sympathetic neurons in oral cancer pain, as well as develop the skills I need to pursue an independent research career.
