Nerve injury (i.e. neuropathic) pain is not well characterized within the Oral Squamous Cell Carcinoma (OSCC) population; a recent pilot study to improve pain phenotyping in oral cancer patients found that the majority of patients report at least one neuropathic pain descriptor, such as “burning” or “pins and needles”. 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 (TGNs) as well as tongue-innervating sympathetic postganglionic neurons in the superior cervical ganglia (SCG). Additionally, in pursuit of the parent grant Specific Aim 2, using single-cell PCR, we found an increase in alpha1-adrenergic receptor gene expression in tongue-innervating TGNs from tumor-bearing mice compared to sham. Furthermore, preliminary data collection by the candidate showed adrenergic sensitivity in tongue-innervating TGNs using Ca2+ imaging; norepinephrine (NE, 10μM) evoked a Ca2+ transient in the majority of tumor mice compared to sham; this NE-evoked response in neurons from tumor-bearing mice was blocked by alpha1-adrenergic receptor antagonist, doxazosin mesylate. While the tumor is still present and cancer-induced nociception is not dependent on sympathetic signaling in its entirety, these data suggest a prominent role for sympathetic neurotransmission in oral cancer pain. The hypothesis for this proposal is that nerve injury secondary to oral cancer dysregulates adrenergic signaling in tongue-innervating nociceptive neurons exacerbating cancer pain. To test this hypothesis using preclinical mouse models, we will determine whether cancer-induced mandibular nerve injury is necessary for the development of adrenergic sensitivity as well as determine whether mandibular nerve injury alone is sufficient for the development of adrenergic sensitivity in the presence of oral cancer, using single-cell PCR, microfluorimetry/electrophysiology and immunohistochemistry. We will also assess the contribution of adrenergic sensitivity in trigeminal afferents to spontaneous orofacial pain behavior (Grimace, and grooming), and leverage adrenergic pharmacology to augment or reduce nociceptive behaviors induced by a model of oral cancer or trigeminal nerve injury.