Abstract Details

This study investigated the mechanism of action of atogepant by assessing its effect on the immediate and delayed activation of mechanosensitive unmyelinated C- and thinly-myelinated Aδ -meningeal nociceptors following cortical spreading depression (CSD). 

Single-unit recordings of activity in trigeminal ganglion neurons (32 Aδ and 20 C-fibers) innervating the dura was used to document change in response to CSD following oral administration of atogepant (5mg/kg) or its vehicle in anesthetized male rats.

While atogepant did not fully prevent activation of nociceptors [incidence of response to CSD in Aδ -fibers (vehicle 73%, atogepant 57%, p=0.42); C-fibers (vehicle 83%, atogepant 56%, p=0.26)], Bayesian analysis of time effects found that it significantly reduced response amplitude and probability of response in both the C- and the Aδ -fibers at different time intervals following CSD induction. For C-fibers, the reduction in responses was significant in the immediate [first hour; -0.29 (90% credible interval (CrI): -0.60 to -0.04)], but not delayed phase of activation, whereas in Aδ -fibers, significant reduction in activation was apparent in the delayed [second hour; -0.53 (90%CrI: -1.0 to -0.05), and third hour -0.57 (90%CrI: -1.0 to -0.1,)] but not early phase of activation.

These findings suggest that atogepant can partially prevent activation of both the Aδ -fiber and C-fiber meningeal nociceptors (by CSD), which differs from results found in similar models for fremanezumab, a CGRP-targeted mAb, and onabotulinumtoxinA.