title: The inimitable kynurenic acid: the roles of different ionotropic receptors in the action of kynurenic acid at a spinal level.
abstract: Kynurenic acid (KYNA) is a neuroactive metabolite that interacts with NMDA, AMPA/kainate and alpha 7 nicotinic receptors. The goal of this study was to clarify the roles of these receptors in the action of KYNA at a spinal level by using highly specific receptor antagonists alone or in triple combinations. Chronic osteoarthritis-like joint pain was induced with monosodium-iodoacetate in male Wistar rats. Mechanical allodynia and motor function were quantified. In the first series we determined the dose-response and time course effects of intrathecally administered KYNA (10-100 μg), D-(-)-2-amino-5-phosphonopentanoic acid (AP5; an NMDA receptor antagonist; 10-200 μg), methyllycaconitine (MLA; an alpha 7 nicotinic receptor antagonist; 100-200 μg) and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzoquinoxaline-7-sulfonamide (NBQX; an AMPA/kainate receptor antagonist; 1-20 μg). In the second series, four different triple combinations of MLA, AP5 and NBQX were investigated. Intrathecal administration of KYNA caused a dose-dependent motor impairment and antinociception. The highly specific NMDA receptor antagonist AP5 caused a motor impairment and antinociception with lower potency. High doses of NBQX resulted in significant antinociception with a slight motor impairment, while only the highest dose of MLA gave rise to significant antinociception with a slight motor impairment. After the coadministration of these ligands as combinations, no potentiation was observed. It may be supposed that the effects of KYNA are primarily due to the inhibition of NMDA receptors at both glycine and phencyclidine (PCP) binding sites, and not to the interactions at the different ionotropic receptors, but the mechanisms behind its high bio-efficiency are still unknown.
authors: Department of Neurology, Faculty of Medicine, University of Szeged, Szeged, Hungary. Electronic address: tuboly.gabor@med.u-szeged.hu.
authors: Gabor
authors: G
authors: Tuboly
authors: Department of Neurology, Faculty of Medicine, University of Szeged, Szeged, Hungary. Electronic address: lillatar@yahoo.com.
authors: Lilla
authors: L
authors: Tar
authors: Department of Neurology, Faculty of Medicine, University of Szeged, Szeged, Hungary. Electronic address: bozsuzso@gmail.com.
authors: Zsuzsanna
authors: Z
authors: Bohar
authors: Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, University of Szeged, Szeged, Hungary. Electronic address: safrany.arpad@stoma.szote.u-szeged.hu.
authors: Arpad
authors: A
authors: Safrany-Fark
authors: Department of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary. Electronic address: petrovszki.zita@med.u-szeged.hu.
authors: Zita
authors: Z
authors: Petrovszki
authors: Department of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary. Electronic address: kekesi.gabriella@med.u-szeged.hu.
authors: Gabriella
authors: G
authors: Kekesi
authors: Department of Neurology, Faculty of Medicine, University of Szeged, Szeged, Hungary; MTA-SZTE Neuroscience Research Group, Hungary. Electronic address: vecsei.laszlo@med.u-szeged.hu.
authors: Laszlo
authors: L
authors: Vecsei
authors: Department of Neurology, Faculty of Medicine, University of Szeged, Szeged, Hungary. Electronic address: pardutz.arpad@med.u-szeged.hu.
authors: Arpad
authors: A
authors: Pardutz
authors: Department of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary. Electronic address: horvath.gyongyi@med.u-szeged.hu.
authors: Gyongyi
authors: G
authors: Horvath
mesh_terms: D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D007461:Iodoacetates; D007736:Kynurenic Acid / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010003:Osteoarthritis / Q000188:drug therapy / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000503:physiopathology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000700:Analgesics; D007461:Iodoacetates; D007736:Kynurenic Acid; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Glutamate receptors; Interaction; Kynurenic acid; Pain; Spinal anesthesia