title: Inhibition of opioid receptor mediated G-protein activity after chronic administration of kynurenic acid and its derivative without direct binding to opioid receptors.
abstract: There is an increasing number of evidence showing analgesic properties of the kynurenic acid (KYNA), and also some studies demonstrate that kynurenine might interact with the opioid system. Therefore in this study, for the first time we investigated the direct binding affinity of KYNA and its structural analog KYNA-1 towards mu, kappa and delta opioid receptor in competition binding experiments applying opioid receptor specific radioligands. The binding affinity measurements were performed in Chinese hamster ovary cell lines overexpressing the corresponding opioid receptor (mu and kappa opioid receptor were rat, delta opioid receptor were mouse sequence). Additionally we also examined the chronic effect of these compounds on mu, kappa and delta opioid receptor and also nociceptin peptide receptor mediated G-protein activity in [(35)S]GTPγS binding assays performed in mouse cortex and striatum membranes. Our results showed that KYNA and KYNA-1 had no affinity towards any of the three classic opioid receptors. On the other hand the compounds significantly decreased opioid and nociceptin receptor mediated G-protein activity or in some cases enhanced the potency of the activating ligand. Moreover, the alterations were receptor and brain region specific. Accordingly, we conclude that KYNA and KYNA-1 do not interact directly with the opioid receptors, but more likely alter the receptor functions intracellularly.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Zador
authors.forename: Reza
authors.initials: R
authors.lastname: Samavati
authors.forename: Eszter
authors.initials: E
authors.lastname: Szlavicz
authors.forename: Bernadett
authors.initials: B
authors.lastname: Tuka
authors.forename: Engin
authors.initials: E
authors.lastname: Bojnik
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fulop
authors.forename: Jozsef
authors.initials: J
authors.lastname: Toldi
authors.forename: Laszlo
authors.initials: L
authors.lastname: Vecsei
authors.affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, H-6701 Szeged, POBox 521, Hungary. borsodi.anna@brc.mta.hu.
authors.forename: Anna
authors.initials: A
authors.lastname: Borsodi
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding / Q000187:drug effects; D011957:Receptors, Opioid / Q000378:metabolism*; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D014162:Transfection
chemical_list: D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D011957:Receptors, Opioid; D013460:Sulfur Isotopes; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019204:GTP-Binding Proteins; D007736:Kynurenic Acid