PROJECT SUMMARY The majority of patients with head and neck squamous cell carcinoma (HNSCC) present with severe pain and increased stress which exceeds the levels seen in other cancers. Due to a multitude of factors, including amplificition 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. The prognostic and long-term effects of cancer stress are unknown. Preliminary data using preclinical mouse models support of the efficacy of beta-adrenergic antagonism using beta-blockers in the treatment of cancer- related pain and progression; we found a reduction in orofacial nociceptive behavior and tumor size in cancer- bearing mice treated with propranolol in their drinking water. In addition, cancer-secreted mediators increased the adrenergic receptor signaling in trigeminal tongue primary afferent neurons as measured by norepinephrine evoked calcium transients. The hypothesis of this proposal is that sympathetic nervous system exacerbates cancer pain and drives tumor progression via local adrenergic signaling in the cancer microenvironment. To test this hypothesis, we will explore the relationship between patient-reported pain, psychological symptom burden (i.e., anxiety, depression, social support), and circulating catecholamine levels in HNSCC patients prior to treatment and through survivorship. We seek to determine if low pre-treatment pain and psychological symptom burden will predeict better patient reported outcomes during survivorship. Using preclinical mouse models of oral cancer, we will investigate the impact of cancer-mediated sensitization on adrenergic signaling in trigeminal primary afferent neurons innervating the tongue in vitro as well as the functional impact of stress on cancer pain behavior and associated peripheral nerve plasticity in vivo. In order to improve outcomes in HNSCC survivors, there is an urgency to better understand the prevelance of pain and stress in HNSCC patients, as well as the underlying biological mechanisms.