Kynurenic acid and its analogue can alter the opioid receptor G-protein signaling after acute treatment via NMDA receptor in rat cortex and striatum

Abstract

Previously, we have shown that the N-methyl d-aspartate (NMDA)-receptor antagonist kynurenic acid (KYNA) and its analogue KYNA1 do not bind directly to mu, kappa and delta opioid receptors in vitro. On the other hand, chronic administration of KYNA and KYNA1 resulted in region (cortex vs striatum) and opioid receptor-type specific alterations in G-protein activation of mouse brain homogenates. Here we describe for the first time the acute effect of KYNA and KYNA1 on opioid receptor function with the possible involvement of the NMDA receptor. The acute 30minute in vivo KYNA1 and KYNA treatments altered opioid receptor G-protein signaling or ligand potency depending on the opioid receptor type and brain region (rat cortex vs striatum) using [S]GTPγS binding assays. Pretreatment with the NMDA receptor antagonist MK-801 impaired or reversed the effects of KYNA1 and KYNA. These results suggest an NMDA receptor mediated effect. After acute 30minute treatment HPLC measurements revealed a similar KYNA1 and a higher KYNA plasma concentration compared to cerebrospinal fluid concentrations. Finally, KYNA, KYNA1 and MK-801 showed comparable results in opioid receptor G-protein activity and ligand potency with acute in vivo treatments when they were administered in vitro for 30min on isolated cortex and striatum slices. We previously demonstrated that KYNA1 and KYNA acutely altered opioid receptor function in vivo and in vitro through the NMDA receptor depending on the opioid receptor type and brain region. This study may lead to a new, indirect approach to influence opioid receptor signaling.

Interactions between the Kynurenine and the Endocannabinoid System with Special Emphasis on Migraine

“…There are extensive data describing the interaction between the kynurenine and the endogenous opioid system [ 60 , 163 , 164 , 165 , 166 , 167 ]. It has also been demonstrated that KYNA and its analog KA1 can indirectly alter the G-protein signaling of opioid receptors through the NMDA receptor depending on the opioid receptor type (μ, κ or δ) and brain region (cortex or striatum) [ 168 , 169 ]. More importantly, the opioid, cannabinoid and the NMDA receptors are known to be co-localized and functionally interact with each other pair-wise in areas relevant to opioid dependence, tolerance and antinociception [ 84 , 142 , 170 , 171 , 172 , 173 , 174 , 175 ].…”

The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain

“…Furthermore, recent research has shed light on the mechanism of emotional learning, including its potential role in modulating affective motor function and emotional responses [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ]. The neural substrates involved in emotional learning, particularly KYNA, suggest a plausible impact on the limbic system, including structures such as the amygdala and prefrontal cortex, which are known to be involved in emotional regulation and associative learning [ 74 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. For example, it has been shown that KYNA and its synthetic analogs, such as SZR-72 and SZR-104, possess the ability not only to influence motor domains of behavior but also to potentially modulate emotional responses [ 87 ].…”

The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs on Motor Domain

“…Furthermore, recent research has shed light on the mechanism of emotional learning, including its potential role in modulating affective motor function and emotional responses [70][71][72][73][74][75][76][77]. The neural substrates involved in emotional learning, particularly KYNA, suggest a plausible impact on the limbic system, including structures such as the amygdala and prefrontal cortex, which are known to be involved in emotional regulation and associative learning [74,[78][79][80][81][82][83][84][85][86]. For example, it has been shown that KYNA and its synthetic analogs, such as SZR-72 and SZR-104, possess the ability not only to influence motor domains of behavior but also to potentially modulate emotional responses [87].…”