Title:Inhibition of Opioid Receptor Mediated G-Protein Activity After Chronic Administration of Kynurenic Acid and its Derivative without Direct Binding to Opioid Receptors
Volume: 13
Issue: 9
Author(s): Ferenc Zador, Reza Samavati, Eszter Szlavicz, Bernadett Tuka, Engin Bojnik, Ferenc Fulop, Jozsef Toldi, Laszlo Vecsei and Anna Borsodi
Affiliation:
Keywords:
[35S]GTPγS binding, G-protein, kynurenic acid, opioid receptors, radioligand binding.
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 [35S]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.
