A novel model of chronic orofacial pain for assessing pain phenotypes and their neural substrates
The 2024 MSC Emerging Science Contest for Early-Career Investigators took place on December 9, 2024. Below is a written summary of one of the presentations from the contest. (A recording of the event is available here).
Category: Pain
Winner: Claudia Daniela Montes Angeles, National Autonomous University of Mexico
Title: A novel model of chronic orofacial pain for assessing pain phenotypes and their neural substrates.
Hypothesis, methodology, findings and conclusions
Our model of chronic orofacial pain consisted of a mental nerve compression injury in wild-type mice; this nerve was exposed and compressed with forceps, sutured and left for recovery. Von Frey testing was performed to assess mechanical sensitivity, one day before, and from day 3 to week 14 after compression. For this assessment, we found that, at week 2, injured mice can be classified into high and low threshold groups, and whether or not they recover their baseline threshold values and when, if that was the case. Most of these mice were classified as high threshold, recovered mice, and they appeared to recover during weeks 3-4 after compression. Therefore, a mental nerve compression nerve injury model is useful to assess chronic orofacial pain phenotypes.
To assess pain-like facial expression, we used in head-fixed video recorded mice, a machine learning-based analysis, from which we found significant differences between a “neutral prototype face” and an evoked pain-like face. Finally, to evaluate the usefulness of our model to look for neural correlates of these phenomena, we used a viral elimination strategy: In genetically engineered mice, we injected a viral vector that contained a caspase that would ablate specific neural populations, for specific brain regions. In this way, we eliminated D1 and D2 receptor-expressing neurons (D1Rn, D2Rn) in the nucleus accumbens (NAc), to assess its effects in the generation of chronic pain phenotypes, as well as glutamatergic neurons in anterior cingulate cortex (ACC), to assess effects on pain-like facial expression after mental nerve injury.
We found that the elimination of the aforementioned neural populations impairs both of the analyzed processes: eliminating D1Rn and D2Rn in NAc increases the proportion of low threshold, non-recovered mice, and eliminating glutamatergic neurons in the ACC impairs the ability of mice to show a pain-like facial expression. Furthermore, inhibiting the ACC with optogenetics techniques also impairs, temporally, the animals’ ability to show such pain-like facial expression.
These results suggest that the mental nerve compression injury model is a useful tool to assess chronic pain phenotypes as well as the neural correlates involved in different processes associated with it. It is of great importance for clinicians to deeply understand these phenomena, since some patients seem to be prone to suffer chronic pain after an injury or a traumatic event, and assessing and discovering the involved neural correlates or the central nervous system landmarks to identify them might allow for improved treatment of, prediction of, or even prevention of chronic pain.
Implications for understanding migraine disease and/or its comorbidities, or how the research holds promise as a new avenue of future migraine study.
This work might be helpful to understand the aforementioned phenomena not only for neuropathic pain, but also for other types of chronic pain such as migraine. It might also advance understanding of the mechanisms that make some subjects more or less susceptible to these phenomena and, therefore, allow for personalized and more effective treatments. Additionally, by being an effective tool for assessing facial expression, this model is also useful for evaluating both the sensory and the affective dimensions of pain, both being severely affected by chronic craniofacial pain.