Background: Head and neck cancer (HNC) patients experience orofacial pain that is exacerbated during function and worsens with disease progression. Current animal models of HNC use ectopic sites for cancer growth and rely on evoked responses to measure pain. Better animal models of HNC and different measures of pain reflecting the human pain experience are needed to enhance our understanding of disease and pain progression and help develop improved therapies to treat the chronic pain associated with HNC.
Advance: NIDCR supported researchers have developed three new models of HNC in rodents that anatomically resemble HNC and in sum, parallel the acute, persistent and chronic phases of HNC pain. In addition, they use a dolognawmeter to measure pain-induced gnawing dysfunction, more faithfully mimicking human HNC pain. Injecting supernatants from human oral squamous cell carcinoma cells or human oral squamous cell carcinoma cells into the tongues of mice, or feeding mice 4-nitroquinoline 1-oxide, a carcinogen, led to increases in orofacial pain for hours, days or weeks, respectively, as measured by the dolognawmeter. Interestingly, in each of these models, either injecting mice locally with inhibitors of trypsin or performing the experiments in transgenic mice lacking the serine protease receptor, PAR2, reduced the orofacial pain associated with acute and persistent models and prevented the development of pain in the chronic pain model, while having no impact on cancer progression. Also, in control mice, PAR2 mRNA and protein were upregulated in the trigeminal ganglion. Further, secretion of the serine protease, trypsin, into the cancer cell environment was increased. The results suggest that PAR2 has a direct role in acute orofacial cancer pain and may be responsible for the development and persistence of chronic orofacial pain in these HNC models.
Public Impact Statement/Significance: The significance of this work lies in the discovery of the role of PAR2 in orofacial pain due to HNC, the development of novel models of HNC more closely mimicking the human condition, and the use of functional measures of orofacial pain. These outcomes, taken together, provide the groundwork for developing new therapeutic approaches aimed at modulating PAR2 activity in the trigeminal system.
Publication Citation: Lam DK, Dang D, Zhang J, Dolan JC and Schmidt, BL (2012). Novel animal models of acute and chronic cancer pain: A pivotal role for PAR2. J Neuroscience, 32(41): 14178-14183. Link to PDF Article: