title: Kappa opioid receptor antagonists: A possible new class of therapeutics for migraine prevention.
abstract: Background Stress is the most commonly reported migraine trigger. Dynorphin, an endogenous opioid peptide acting preferentially at kappa opioid receptors (KORs), is a key mediator of stress responses. The aim of this study was to use an injury-free rat model of functional cephalic pain with features of migraine and medication overuse headache (MOH) to test the possible preventive benefit of KOR blockade on stress-induced cephalic pain. Methods Following sumatriptan priming to model MOH, rats were hyper-responsive to environmental stress, demonstrating delayed cephalic and extracephalic allodynia and increased levels of CGRP in the jugular blood, consistent with commonly observed clinical outcomes during migraine. Nor-binaltorphimine (nor-BNI), a long-acting KOR antagonist or CYM51317, a novel short-acting KOR antagonist, were given systemically either during sumatriptan priming or immediately before environmental stress challenge. The effects of KOR blockade in the amygdala on stress-induced allodynia was determined by administration of nor-BNI into the right or left central nucleus of the amygdala (CeA). Results KOR blockade prevented both stress-induced allodynia and increased plasma CGRP. Stress increased dynorphin content and phosphorylated KOR in both the left and right CeA in sumatriptan-primed rats. However, KOR blockade only in the right CeA prevented stress-induced cephalic allodynia as well as extracephalic allodynia, measured in either the right or left hindpaws. U69,593, a KOR agonist, given into the right, but not the left, CeA, produced allodynia selectively in sumatriptan-primed rats. Both stress and U69,593-induced allodynia were prevented by right CeA U0126, a mitogen-activated protein kinase inhibitor, presumably acting downstream of KOR. Conclusions Our data reveal a novel lateralized KOR circuit that mediated stress-induced cutaneous allodynia and increased plasma CGRP in an injury-free model of functional cephalic pain with features of migraine and medication overuse headache. Selective, small molecule, orally available, and reversible KOR antagonists are currently in development and may represent a novel class of preventive therapeutics for migraine.
authors.affiliation: 1 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Xie
authors.affiliation: 2 School of Clinical Dentistry, University of Sheffield, Sheffield, UK.
authors.forename: Milena
authors.initials: M
authors.lastname: De Felice
authors.affiliation: 3 Department of Pharmacology, Biological Sciences Section, Federal University of Parana, Curitiba, Brazil.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Kopruszinski
authors.affiliation: 1 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Eyde
authors.affiliation: 1 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: LaVigne
authors.affiliation: 1 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Bethany
authors.initials: B
authors.lastname: Remeniuk
authors.affiliation: 1 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Hernandez
authors.affiliation: 1 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Yue
authors.affiliation: 1 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Goshima
authors.affiliation: 1 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ossipov
authors.affiliation: 4 Department of Biomedical Sciences, College of Osteopathic Medicine, Center for Excellence in the Neurosciences, University of New England, Biddeford, ME, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: King
authors.affiliation: 1 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Streicher
authors.affiliation: 1 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Edita
authors.initials: E
authors.lastname: Navratilova
authors.affiliation: 5 Mayo Clinic, Phoenix, AZ USA.
authors.forename: David
authors.initials: D
authors.lastname: Dodick
authors.affiliation: 6 Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.affiliation: 6 Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Ed
authors.initials: E
authors.lastname: Roberts
authors.affiliation: 1 Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA.|5 Mayo Clinic, Phoenix, AZ USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008881:Migraine Disorders; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*
chemical_list: D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone
keywords: Kappa opioid receptor antagonists; amygdala; migraine; prophylaxis; stress