title: Prevention of stress- or nitric oxide donor-induced medication overuse headache by a calcitonin gene-related peptide antibody in rodents.
abstract: Objective The objective of this study was the determination of the role of calcitonin gene-related peptide (CGRP) in the induction of medication overuse headache (MOH)-related migraine in an injury-free preclinical model. Methods Rats were primed by a 7-day period of exposure to acute migraine therapies including sumatriptan and morphine. After an additional 14-day drug-free period, rats were exposed to putative migraine triggers including bright light stress (BLS) or nitric oxide (NO) donor in the presence or absence of TEV48125, a fully humanized CGRP antibody. Cutaneous allodynia (CA) was used as an outcome measure and CGRP blood and cerebrospinal fluid (CSF) levels were measured. Results BLS and NO donor challenge evoked delayed, long-lasting CA selectively in rats that were previously treated with sumatriptan or morphine. BLS produced a significant increase in CGRP in the plasma, but not CSF, in animals that were previously exposed to sumatriptan compared to saline controls. TEV48125 did not modify baseline tactile thresholds or produce behavioral side effects, but significantly inhibited both BLS- and NO donor-induced CA in animals that were previously primed with sumatriptan or morphine; an isotype control protein that does not bind CGRP had no effect. Interpretation These data suggest that acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and that anti-CGRP antibodies may be a useful clinical strategy for the treatment of MOH.
authors.affiliation: 1 Department of Pharmacology, Biological Sciences Section, Federal University of Parana, Curitiba, Brazil.
authors.forename: Caroline Machado
authors.initials: CM
authors.lastname: Kopruszinski
authors.affiliation: 2 Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Jennifer Yanhua
authors.initials: JY
authors.lastname: Xie
authors.affiliation: 2 Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Nathan Mackenzie
authors.initials: NM
authors.lastname: Eyde
authors.affiliation: 3 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Bethany
authors.initials: B
authors.lastname: Remeniuk
authors.affiliation: 4 Antiva Biosciences, Inc., South San Francesco, CA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Walter
authors.affiliation: 5 Teva Biologics R&D, Redwood City, CA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stratton
authors.affiliation: 4 Antiva Biosciences, Inc., South San Francesco, CA, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Bigal
authors.affiliation: 1 Department of Pharmacology, Biological Sciences Section, Federal University of Parana, Curitiba, Brazil.
authors.forename: Juliana Geremias
authors.initials: JG
authors.lastname: Chichorro
authors.affiliation: 6 Mayo Clinic, Phoenix, AZ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dodick
authors.affiliation: 2 Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.|4 Antiva Biosciences, Inc., South San Francesco, CA, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051271:Headache Disorders, Secondary / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D006930:Hyperalgesia / Q000378:metabolism; D008297:Male; D020030:Nitric Oxide Donors / Q000633:toxicity*; D010775:Photic Stimulation / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism*; D018170:Sumatriptan / Q000633:toxicity
chemical_list: D000911:Antibodies, Monoclonal; D020030:Nitric Oxide Donors; C000604315:fremanezumab; D018170:Sumatriptan; D015740:Calcitonin Gene-Related Peptide
keywords: CGRP antibody; Migraine; TEV48125; medication overuse headache; rats