Dissecting the Heterogeneity of Oral Cancer Pain

Oral squamous cell carcinoma (SCC) is the sixth most common cancer worldwide. The majority of patients with oral SCC suffer from severe, chronic, function-induced pain. Despite the severity of pain in many patients, the presentation of oral cancer pain is variable. Opioids are the only treatment available for oral cancer pain. Opioids are often ineffective and associated with tolerance, constipation, somnolence, respiratory depression, and addiction, which is now a national crisis. The current hypothesis for the etiology of oral cancer pain, which is based on clinical studies utilizing questionnaires and preclinical studies, is that cancer cells and cells within the microenvironment produce mediators that activate and sensitize nociceptors. Published and preliminary data indicate that cancer-secreted mediators induce mechano- and chemosensitivity. For example, preliminary clinical studies demonstrate that oral cancer patients experience preoperative sensitivity to capsaicin (i.e., chemosensitivity) and report greater functional (i.e., mechanosensitivity) pain. Capsaicin activates transient receptor potential vanilloid 1 (TRPV1). TRPV1 is activated by temperatures above 43°C and endogenous lipid metabolic products. Mice deficient in TRPV1 respond to mechanical stimuli, suggesting that TRPV1 is not involved in the detection of mechanical stimulation. By contrast, TRP ankyrin repeat 1 (TRPA1), co-localized with TRPV1, is responsive to mechanical stimuli, in addition to irritants such as allyl isothiocyanate (AITC). Both TRPV1 and TRPA1 have been reported to play important roles in orofacial pain. Improved knowledge of the contribution of TRPV1 and TRPA1 to oral cancer pain holds considerable promise for the development of novel, non-opioid treatment strategies that specifically address the unique pain experience of individual patients. There is a lack of published data characterizing the sensory phenotype of tumor-related cancer pain, which has significant implications for understanding the underlying pathophysiological mechanisms of cancer pain. Quantitative sensory testing can provide insight into the mechanism(s) responsible for pain. In this proposal, we will test our hypothesis that the quality of pain experienced by oral cancer patients is dependent on the level of activation of specific channels on nociceptors. We will perform mechanical (von Frey testing) and chemical sensitivity tests (sensitivity to capsaicin, TRPV1 agonist, and AITC (TRPA1 agonist) on oral cancer patients, and compare the sensitivities to healthy subjects. For cancer patients, we will administer the validated University of California San Francisco (UCSF) Oral Cancer Pain Questionnaire to evaluate the correlation between mechanical and chemical thresholds with relevant aspects of pain. We propose that the quality of pain experienced by oral cancer patients is quantifiable and dependent on the level of sensitization and activation of specific channels on nociceptors.