title: Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: Targets and anti-migraine mechanisms.
abstract: Background Trigeminal sensitization represents a major mechanism underlying migraine attacks and their recurrence. Nitroglycerin (NTG) administration provokes spontaneous migraine-like headaches and in rat, an increased sensitivity to the formalin test. Kynurenic acid (KYNA), an endogenous regulator of glutamate activity and its analogues attenuate NTG-induced neuronal activation in the nucleus trigeminalis caudalis (NTC). The anti-hyperalgesic effect of KYNA analogue 1 (KYNA-A1) was investigated on animal models specific for migraine pain. Aim Rats made hyperalgesic by NTG administration underwent the plantar or orofacial formalin tests. The effect of KYNA-A1 was evaluated in terms of nocifensive behavior and of neuronal nitric oxide synthase (nNOS), calcitonin gene-related peptide (CGRP) and cytokines expression in areas involved in trigeminal nociception. Results KYNA-A1 abolished NTG-induced hyperalgesia in both pain models; NTG alone or associated to formalin injection induced an increased mRNA expression of CGRP, nNOS and cytokines in the trigeminal ganglia and central areas, which was reduced by KYNA-A1. Additionally, NTG caused a significant increase in nNOS immunoreactivity in the NTC, which was prevented by KYNA-A1. Conclusion Glutamate activity is likely involved in mediating hyperalgesia in an animal model specific for migraine. Its inhibition by means of a KYNA analogue modulates nNOS, CGRP and cytokines expression at peripheral and central levels.
authors.affiliation: 1 Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Greco
authors.affiliation: 1 Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy.|2 Department of Brain and Behavior, University of Pavia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Demartini
authors.affiliation: 1 Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy.|2 Department of Brain and Behavior, University of Pavia, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Zanaboni
authors.affiliation: 1 Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Redavide
authors.affiliation: 1 Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Selena
authors.initials: S
authors.lastname: Pampalone
authors.affiliation: 3 Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Hungary.
authors.forename: Joseph
authors.initials: J
authors.lastname: Toldi
authors.affiliation: 4 Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Szeged, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.affiliation: 5 Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Blandini
authors.affiliation: 1 Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nappi
authors.affiliation: 1 Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy.|2 Department of Brain and Behavior, University of Pavia, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sandrini
authors.affiliation: 6 Department of Neurology, MTA-SZTE Neuroscience Research Group, University of Szeged, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Vécsei
authors.affiliation: 1 Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy.|2 Department of Brain and Behavior, University of Pavia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tassorelli
mesh_terms: D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D008297:Male; D008881:Migraine Disorders / Q000378:metabolism; D005996:Nitroglycerin / Q000633:toxicity; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000633:toxicity
chemical_list: D018691:Excitatory Amino Acid Antagonists; D014665:Vasodilator Agents; D005996:Nitroglycerin; D007736:Kynurenic Acid
keywords: KYNA amides; hyperalgesia; migraine; nitroglycerin