Peripheral and central mechanisms of migraine provide rationale for combination therapy

The purpose of this study was to determine the effects of BoNT-A/atogepant (ATO) combination treatment on activation/sensitization of high-threshold (HT) and wide-dynamic range (WDR) trigeminovascular neurons in the spinal trigeminal nucleus (STN) by CSD. ATO is a small molecule CGRP receptor antagonist. (A) Individual analysis: in the control group, CSD activated 80% of HT and 70% of WDR neurons whereas in the treatment group it activated 10% of HT (p = 0.001, c² = 9.8) and 0% of WDR (p = 0.001, c² = 10.7) neurons. Similarly, in the control group, CSD sensitized 80% of HT and 60% of WDR neurons whereas in the treatment group it sensitized 0% of HT and 5% of WDR neurons. (B) Group analysis: statistical analyses of all neurons revealed that in the control group, spontaneous activity increased significantly in both HT (c² = 6.4, p = 0.039) and WDR (c² = 7.8, p = 0.004) neurons, whereas in the treatment group it remained unchanged in the HT (c² = 1.4, p = 0.35) and decreased, rather than increased, significantly (c² = 8.6, p = 0.003) in the WDR neurons. A similar pattern was seen in responses to mechanical stimulation of the dura and skin. Given BoNT-A preferential inhibitory effects on unmyelinated C- but not thinly myelinated Ad-fibers, and fremanezumab preferential inhibitory effects on Ad- but not C-fibers, it is reasonable to propose that the robust inhibition of activation and sensitization of the HT and WDR trigeminovascular neurons by the BoNT-A/ATO combination treatment was achieved through a dual blockade of both classes of meningeal nociceptors.