Inhibition of Opioid Receptor Mediated G-Protein Activity After Chronic Administration of Kynurenic Acid and its Derivative without Direct Binding to Opioid Receptors.

Zádor, Ferenc and Samavati, Reza and Szlávicz, Eszter and Tuka, Bernadett and Bojnik, Engin and Toldi, József and Vécsei, László and Borsodi, Anna (2014) Inhibition of Opioid Receptor Mediated G-Protein Activity After Chronic Administration of Kynurenic Acid and its Derivative without Direct Binding to Opioid Receptors. CNS AND NEUROLOGICAL DISORDERS. DRUG TARGETS, 13 (9). pp. 1520-1529. ISSN 1871-5273

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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]GTPgammaS 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.

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