Manual and Automated Capture of Analgesic-Responsive Facial Pain Behaviors of Unrestrained Mice in a Trigeminal Neuralgia Model.

ABSTRACT:Trigeminal neuralgia (TN), a devastating neuropathic pain condition, profoundly affects human well-being. Despite an initial response to carbamazepine (CBZ), many patients become refractory to pharmacotherapy and subsequent invasive procedures. Although preclinical trigeminal neuropathic pain models following extracranial chronic constriction injury (CCI) of the trigeminal nerve have been developed, the injury-induced facial hypersensitivity is rarely CBZ-responsive, questioning the models' relevance to TN. In recent reports, CBZ-responsive facial pain can be induced by intracranial CCI that better mimics the compression observed in classical TN. Nevertheless, behavioral assessment of persistent pain in these models often requires a restrained setting that could trigger unpredictable behaviors that are not necessarily pain associated. Here, we focused on spontaneous and evoked measures of pain in unrestrained mice after a CBZ-sensitive intracranial CCI, namely the FRICT-ION model. To measure these behaviors long-term, we developed a high-frame rate videography analysis that reliably captures increased chronic spontaneous asymmetric grooming and mechanically evoked facial rubbing, ipsilateral to the injury. Notably, this altered behavioral phenotype was significantly reversed by a nonsedating dose of CBZ. Using DeepLabCut tracking, we also found that the speed of head movement after facial mechanical stimulation is a significant CBZ-sensitive behavioral correlate of TN allodynia. Importantly, these behavioral measures accurately recapitulated the clinical outcomes-both success and failure-of a cohort of specific nonopioid analgesics that have previously been tested in the clinical management of TN. Together, these measures should greatly facilitate the research development of innovative TN therapies.