Extracranial Injections of OnabotulinumtoxinA in Combination with Intravenous Injection of Atogepant Attenuates Activation and Sensitization of HT and WDR Neurons by CSD (4287)

Objective: To determine the effects of a combination therapy with BoNT-A and atogepant (Ato) on the responsiveness of central trigeminovascular neurons (in SpV) to CSD. Background: We showed recently that cortical spreading depression (CSD) activates 2 distinct trigeminovascular pathways, one that is blocked by CGRP-mAbs, consisting of peripheral Ad nociceptors and central high-threshold (HT) neurons, and a second one that is blocked by onabotulinumtoxinA (BoNT-A), consisting of peripheral C-fiber and central wide-dynamic-range (WDR) neurons. Design/Methods: In the BoNT-A/Ato experiments, we studied responses to a single wave of CSD in 22 SpV dura-sensitive neurons (11 HT, 11 WDR) of animals treated with saline (injected 7–11d before recording) and vehicle (PEG 400) injected iv 1h before CSD (control group), or BoNT-A and Ato injected at same timepoints (BoNT-A/Ato group). Results: All neurons: In control animals, a single wave of CSD activated 70% of all central trigeminovascular neurons, whereas in the BoNT-A/Ato group, it activated only 8.3% (X2= 0.002). In the control group, mean firing increased >230% 1 and 2h after CSD. In the BoNT-A/Ato group, mean firing remained unchanged after CSD. HT neurons: CSD activated 80% of the neurons in the control group, and 16.6% in the BoNT-A/Ato group (X2= 0.035). The mean firing increased 162.1 (1h) and 251.1% (2h) after CSD in the control group and remained unchanged in the BoNT-A/Ato group. WDR neurons: CSD activated 60% of the neurons in the control group, and 0% in the BoNT-A/Ato group (X2= 0.026). The mean firing increased 542.9 (1h) and 199.4% (2h) after CSD in the control group and remained unchanged in the BoNT-A/Ato group. Conclusions: The findings raise the possibility that chronic migraine patients may benefit from treatment approach that combines drugs that block the trigeminovascular Ad-HT pathway (i.e., Ato or any other CGRP modulator) and the C-WDR pathway (i.e., BoNT-A). Disclosure: Dr. Melo Carrillo has nothing to disclose. Dr. Strassman has nothing to disclose. Dr. Schain has nothing to disclose. Dr. Manack Adams has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Aubrey Manack Adams, PhD, is a full-time employee of Allergan plc and owns stock in the company.. Dr. Manack Adams has received compensation for serving on the Board of Directors of Aubrey Manack Adams, PhD, is a full-time employee of Allergan plc and owns stock in the company.. Dr. Manack Adams holds stock and/or stock options in Aubrey Manack Adams, PhD, is a full-time employee of Allergan plc and owns stock in the company. which sponsored research in which Dr. Manack Adams was involved as an investigator. Dr. Manack Adams holds stock and/or stock options in Aubrey Manack Adams, PhD, is a full-time employee of Allergan plc and owns stock in the company.. Dr. Manack Adams has received research support from Aubrey Manack Adams, PhD, is a full-time employee of Allergan plc and owns stock in the company.. Dr. Brin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Allergan plc. Dr. Brin holds stock and/or stock options in Allergan plc which sponsored research in which Dr. Brin was involved as an investigator. Dr. Brin holds stock and/or stock options in Allergan plc.Dr. Burstein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder, Allergan, Novartis, Biohaven, Dr. Reddy Laboratories, Electrocore, Johnso & Johnson, Neurolief, teva, Theranica. Dr. Burstein has received research support from Allergan, TEVA, Dr. Reddy..