Oral atogepant mitigates spreading depolarization-induced pain and anxiety behavior in mice.

Background: Spreading depolarization (SD) is the most likely cause of migraine aura and may be linked to trigeminal nociception. Using minimally invasive optogenetic SD induction (opto-SD), we previously showed that SD triggers acute periorbital mechanical allodynia-like behavior, supporting SD-induced activation of migraine-relevant trigeminal pain pathways. Here, we tested whether selective oral calcitonin gene-related peptide (CGRP) receptor antagonist, atogepant, could ameliorate SD-evoked pain and anxiety phenotypes.

Methods: Thirty-two adult male and female Thy1-ChR2-EYFP transgenic mice (3-5 months, 18-30 g) housed in 12/12-hr light/dark cycles were used. Under brief isoflurane anesthesia, a thin glass panel was placed on intact skull one week before the experiment to achieve translucency. A single SD was evoked using 10 s, 10 mW blue light stimulation over the motor cortex. One hour before SD or sham stimulation, atogepant (ato; 30 mg/kg in 100% PEG400) or vehicle (veh; 100% PEG400) was administered by oral gavage (4 mL/kg). Mechanical periorbital thresholds were measured 1 h after SD using von Frey monofilaments. Mouse grimace was then quantified using PainFace, an open convolutional neural network platform. Lastly, anxiety-like behavior was examined in an open field. Groups were randomly assigned and the investigator blinded to group allocation (n = 8/group, balanced by sex), p < 0.05 was considered significant.

Results: There was a significant main effect of SD (p < 0.001) and atogepant (p = 0.015) on the periorbital threshold with an interaction (p < 0.001). A single opto-SD lowered periorbital threshold compared with sham (veh sham vs. veh SD: p < 0.001). SD also increased the total grimace score compared with sham (veh sham vs. veh SD: p = 0.014). Oral atogepant (30 mg/kg) alleviated SD-induced periorbital allodynia-like behavior (veh SD vs. ato SD: p < 0.001) but did not completely reverse SD-induced periorbital allodynia-like behavior (ato sham vs. ato SD: p < 0.001). Atogepant abolished the SD-induced facial grimace (ato sham vs. ato SD: p = 0.238). SD increased thigmotaxis score compared with sham (veh sham vs. veh SD: p = 0.016). Following atogepant treatment, there was no difference in thigmotaxis score in SD versus sham groups (ato sham vs. ato SD: p = 0.200).

Conclusions: These data suggest SD provokes a reproducible and robust facial pain phenotype in mice that is alleviated by pre-administration with atogepant. There was also improvement in SD-induced anxiety-like behavior following atogepant.