Atogepant – an orally-administered CGRP antagonist – attenuates activation of meningeal nociceptors by CSD

Author:

Strassman Andrew M12,Melo-Carrillo Agustin12,Houle Timothy T3,Adams Aubrey3,Brin Mitchell F45ORCID,Burstein Rami12

Affiliation:

1. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center

2. Harvard Medical School, Boston, Massachusetts, USA

3. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, USA

4. Allergan, an AbbVie Company, Irvine, CA, USA

5. Dept of Neurology, University of California, Irvine, USA

Abstract

Background This study investigated the mechanism of action of atogepant, a small-molecule CGRP receptor antagonist recently approved for the preventive treatment of episodic migraine, by assessing its effect on activation of mechanosensitive C- and Aδ-meningeal nociceptors following cortical spreading depression. Methods Single-unit recordings of trigeminal ganglion neurons (32 Aδ and 20 C-fibers) innervating the dura was used to document effects of orally administered atogepant (5 mg/kg) or vehicle on cortical spreading depression-induced activation in anesthetized male rats. Results Bayesian analysis of time effects found that atogepant did not completely prevent the activation of nociceptors at the tested dose, but it significantly reduced response amplitude and probability of response in both the C- and the Aδ-fibers at different time intervals following cortical spreading depression induction. For C-fibers, the reduction in responses was significant in the early phase (first hour), but not delayed phase of activation, whereas in Aδ-fibers, significant reduction in activation was apparent in the delayed phase (second and third hours) but not early phase of activation. Conclusions These findings identify differences between the actions of atogepant, a small molecule CGRP antagonist (partially inhibiting both Aδ and C-fibers) and those found previously for fremanezumab, a CGRP-targeted antibody (inhibiting Aδ fibers only) and onabotulinumtoxinA (inhibiting C-fibers only)- suggesting that these agents differ in their mechanisms for the preventive treatment of migraine.

Funder

AbbVie

National Institute of Neurological Disorders and Stroke

Publisher

SAGE Publications

Subject

Neurology (clinical),General Medicine

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