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

Abstract

Both the kynurenine and the endocannabinoid systems are involved in several neurological disorders, such as migraine and there are increasing number of reports demonstrating that there are interactions of two systems. Although their cooperation has not yet been implicated in migraine, there are reports suggesting this possibility. Additionally, the individual role of the endocannabinoid and kynurenine system in migraine is reviewed here first, focusing on endocannabinoids, kynurenine metabolites, in particular kynurenic acid. Finally, the function of NMDA and cannabinoid receptors in the trigeminal system-which has a crucial role in the pathomechanisms of migraine-will also be discussed. The interaction of the endocannabinoid and kynurenine system has been demonstrated to be therapeutically relevant in a number of pathological conditions, such as cannabis addiction, psychosis, schizophrenia and epilepsy. Accordingly, the cross-talk of these two systems may imply potential mechanisms related to migraine, and may offer new approaches to manage the treatment of this neurological disorder.

Keywords: cannabinoid receptors; cannabinoids; endocannabinoids; kynurenines; migraine; opioids.

Figure 1

The kynurenine pathway. The most relevant metabolites of the pathway are highlighted in different colors, and the key enzymes are also represented on the arrows. Dashed arrows indicate the indirect linkage between the kynurenine and serotonin pathway. The two sequentially arrows symbolizes the multiple (not indicated) steps in quinolinic acid metabolization to nicotinamide adenine dinucleotide (NAD⁺). Abbreviations: IDO (indoleamine 2,3-dioxygenase); KATs (kynurenine aminotransferases); KMO (l-kynurenine 3-monooxygenase); KYNU (l-kynurenine hydrolase); NAD⁺ (nicotinamide adenine dinucleotid), TDO (tryptophan 2,3-dioxygenase).

Figure 2

The type 1 cannabinoid receptor-N-methyl-d-aspartate (CB1-NMDA) receptor complex and potential pharmacological targets to reduce N-methyl-d-aspartate (NMDA) receptor hyperactivity, which is one of the main pathomechanism of migraine. The pharmacological inhibition (red arrow) of endocannabinoid metabolizing enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) (1) increases (upward green arrow) endocannabinoid levels (e.g., 2-arachidonoylglycerol (2-AG), anandamide (AEA)) (2) [113], thus enhancing the agonist-mediated type 1 cannabinoid receptor (CB1) receptor activity (3) (in this step the black arrows indicate ligand binding). This mechanism will overall reduce (red arrow) the activity of the NMDA receptor, hence the risk of excitotoxicity via CB1 receptor and the σ1R-HINT1 protein tandem (4) [124,153,154]. Exogenous ligands can also induce CB1-receptor mediated NMDA receptor inhibition more effectively (3,4) [124]. Additionally, exogenous cannabinoids such as cannabidiol or Δ9-tetrahydrocannabinol are known to stimulate (blue arrow) the indoleamine 2,3-dioxygenase (IDO) enzyme activity in dependence of cannabinoid receptor activation (5) [120]. This stimulation, together with the pharmacological inhibition (red arrow) of the kynurenine 3-monooxygenase (KMO) enzyme (6) [123] may enhance (yellow upward arrow) endogenous KYNA levels indirectly (indicated by dashed lines), through the kynurenine pathway (7) (Figure 1), which will result an enhanced reduction in NMDA receptor activity via the antagonizing effect (black arrow) of kynurenic acid (KYNA) (8).The figure shows a simplified, hypothetical scenario of the indicate elements and mechanisms of the endocannabinoid and kynurenine system within the CB1-NMDA receptor complex, which has been individually reported previously in other circumstances (cited accordingly). The figure also indicates the sigma 1 receptors- histidine triad nucleotide-binding protein 1 (σ1R-HINT1) protein tandem, which associates the two receptors and it is based on Rodriguez-Munoz and co-worker’s review [124]. NR1 and NR2 indicate the two types of subunit of the NMDA receptor and the C terminus of the CB1 receptor is also highlighted. The green color indicates endocannabinoid, while the yellow color indicates kynurenine system related ligands, receptors, enzymes or mechanisms. The shapes of the indicated ligands, receptors or enzymes are schematic or overly simplified representations of their structures.