Seminars

Chronic neuropathic orofacial pain (CNOP) can be produced by surgical interventions, and it is detrimental for the quality of life of who suffer from it. The development of an experimental model similar to its clinical features is necessary for a precise approach to the study of its neurobiological basis. We propose the mental nerve compression injury as a useful model for studying different phenomena that occur in the development of such disease, from behavior for identifying phenotypes, to analyze facial expression, as well as to assess the neural substrates involved. Wild-type (WT) mice went through mental nerve compression injury to induce CNOP, and were assessed with von Frey test, for nociceptive threshold on day 3 to week 14. To determine the role of nucleus accumbens (NAc) dopamine-receptor-expressing neurons (DRn), D1- and D2R-Cre mice were infected with a genetically engineered caspase in NAc, causing specific ablation of such neurons. Mechanical sensitivity was tested before and after it, and after nerve injury. For facial expression analysis, WT mice were face-recorded in a head-fixed system during the onset of mechanical stimulation, at -1, 4 and 7 days after nerve injury; electrophysiological recordings were performed in anterior cingulate cortex (ACC). In vglut2-ires-cre mice ACC neurons were ablated in a Caspase-dependent manner. Videos were analyzed with an artificial-vision tool; firing rate z-score was calculated and analyzed with a Generalized Lineal Model to identify neurons modulated by the pain facial response. We found that injured WT mice showed mechanical hypersensitivity during the first weeks. Mice were classified in high and low threshold (HT and LT), being most of them HT mice. Most HT mice recovered from mechanical hypersensitivity, whereas most LT mice remained hypersensitive. NAc DRn ablation decreased the percentage of HT mice and increased the time of hypersensitivity recovery, suggesting this population participates in nociceptive threshold profiles and recovery capacity. The painful facial response is dependent on the stimuli force and it is exacerbated by the mental nerve lesion. GLM analysis detected a neural population modulated by the pain facial response for both stimuli, that increased its firing rate after the stimuli onset. ACC neural ablation showed no effect on the baseline facial response but abolished the changes observed in the context of neuropathic pain. This way, we found that mental nerve compression injury produces two chronic pain development phenotypes, is functional for the analysis of facial expression through artificial vision tools, and for the assessment of the neural structures involved.