A study on the correlation of the asymmetric regulation between the periaqueductal gray and the bilateral trigeminal nucleus caudalis in migraine male rats

The current study was designed to explore the correlation of the asymmetric regulation between the periaqueductal gray (PAG) and the bilateral trigeminal nucleus caudalis (TNC) in migraine rats through the changes of metabolites and neurotransmitters of PAG and TNC in the pain regulatory pathway of acute migraine attack. In our study, we found that the metabolites and neurotransmitters of the PAG, the LTNC and the RTNC had interaction effects between groups and sites. The concentration of the rLac of the PAG, LTNC and RTNC increased in migraine rats, however, the rLac of the LTNC and the RTNC increased more than that of the PAG. Besides, the concentrations of metabolites and neurotransmitters were asymmetrical in the LTNC and the RTNC which showed that the rNAA and rGln increased in the RTNC, while rGABA decreased in the RTNC. Therefore, we can conclude that there is a correlation between the PAG, LTNC and RTNC in the regulation of pain during the acute attack of migraine, and the regulation of the LTNC and RTNC on pain is asymmetric.

Our study found that the rLac increased in PAG, RTNC, and LTNC in migraine rats. Lac is the product of anaerobic glycolysis. The increase of Lac in the brain is thought to be caused by mitochondrial dysfunction or insufficient oxygen content [20]. However, in recent years, it has been found that increased neuronal activity can lead to a rapid and transient increase of Lac in brain [21]. In addition, it has also been found that Lac increases in the occipital cortex and cerebellum during the interval of migraine attacks [22,23,24,25]. TNC is an important structure for nociceptive generation, so when pain stimuli are transmitted to TNC, the neuronal activity of TNC increases, which leads to the increase of Lac in TNC on both sides, suggesting that TNC neurons are activated bilaterally. PAG is the core part of the central endogenous analgesic system, in the early stage of migraine attack, the Lac of PAG increased less than that of TNC which suggests that the neuronal activity of PAG also increased less than that of TNC, indicating that PAG neurons respond to pain in the early stage, however, it needs further investigation whether this early response promotes pain or involved in pain suppression.

Our study also found that rNAA increased on RTNC in migraine rats, whereas rNAA did not show such a difference on LTNC. NAA is synthesized by aspartic acid and acetyl-CoA (CoA) under the catalysis of aspartic acid N-acetyltransferase [26], which is mainly concentrated in gray matter rich areas in the brain [27]. The synthesis of NAA depends on the integrity of neuronal mitochondria, and the fluctuation of concentration of NAA may occur simultaneously with the change of adenosine triphosphate (ATP) which suggests that it is closely related to metabolic energy [28, 29]. As a result, when neurons are stimulated, NAA will be released [30]. TNC is an important structure for nociceptive production, which contains a relatively rich ratio of neurons to glial cells, during pain stimulation, neurons release a large amount of stored NAA, which increases its concentration transiently. However, in our study, there is no similar phenomenon on LTNC and PAG which is an interesting phenomenon, According to Lac, we can know that bilateral TNC and PAG have activation changes in the early stage of migraine, but NAA, as a marker of neuronal activity, only increases in RTNC, therefore, it needs further study whether NAA is an important marker of neuronal activation related to pain generation or transmission. At the same time, this phenomenon also suggests that TNC on both sides have differences in conduction of pain sensation when exposed to pain stimuli.

In our study, we also found that rGABA decreased and Gln increased in RTNC of migraine rats. Gln is a metabolite of the excitatory neurotransmitter glutamate (Glu), specifically produced in brain astrocytes by glutamate and ammonia under the catalysis of glutamine synthetase. Then, glutamine is transported back to neurons, where it is converted to Glu by mitochondrial glutaminase [31]. This circulation is thought to prevent neuroexcitability caused by the production of too much Glu in the brain. GABA is a major inhibitory neurotransmitter in the central nervous system, which is directly synthesized by Glu through glutamate decarboxylase [32]. Meanwhile, the imbalance of Glu-GABA concentration has been considered as another hypothesis for the occurrence of migraine [33]. Zhe Ma et al. [18] found a significant increase of Glu/GABA+ in the thalamus of migraine rats, whereas Nastaren Abad et al. [19] did not find the similar increase in cortical regions of the migraine rat. The increased Gln in our study may be due to the rapid action of the excitatory neurotransmitter Glu early in migraine attack, causing pain to occur and producing excessive Gln. At the same time, when the pain stimulus is transmitted to the RTNC, the inhibitory neurotransmitter GABA decreases which reduces the pain threshold and improves the excitability of RTNC, and thus accelerates the conduction of pain stimulus signal.

In addition, our study found that the relative concentrations of brain metabolites rNAA, rGlu, rGln and rTau in the PAG and the bilateral TNC had interaction effects between groups and sites. However, the interaction effect could not be proved by current experiments and its significance needs to be further studied.

Our study identified asymmetric changes of metabolic substances and neurotransmitters in the left and right TNC during headache attack in a migraine rat model, which was first found in the study of migraine attack mechanism. These asymmetrical changes are consistent with our recent clinical findings which is that some migraine patients with patent foramen ovale (PFO) often have long-term unilateral headache, in recent years, many researches [34,35,36] have identified a relationship between PFO and migraine headache which also indirectly suggests the possibility of bilateral asymmetric regulation of migraine. In addition to that, Momoh-Ojewuyi et al. [37] found that a small percentage of people experienced long-term migraine with unilateral fixation, which is called side locked unilateral headache (SLUH). Besides, Shinoura N et al. [38] found that stress-related vascular responses were suppressed in the right cerebral hemisphere during migraine interictal periods, which indirectly suggested left-right cerebral functional asymmetry in migraine mechanisms. In addition, this functional asymmetry has been studied in other disorders, for example, antidepressants can increase activity in the left hemisphere [39, 40], Kong XZ et al. [41] have also shown that autism spectrum disorder (ASD) is associated with a subtle reduction in cortical thickness asymmetry that is widely distributed in cortical regions. Therefore, asymmetric regulation of brain function has been gradually discovered and studied in some diseases. Finally, our study points out that there are asymmetric changes of metabolites in left and right TNC during migraine attacks, these asymmetrical changes are consistent with Momoh-Ojewuyi et al’s found [37] which not only provides a new insight into the clinical application of unilateral nerve electrical stimulation in the treatment of migraine when drugs cannot provide sufficient relief, but also provides a new direction for future research on the pathogenesis of migraine.

In this study, the rat model of migraine was induced by GTN which mimic those migraine patients caused by meningeal inflammation and dural mast cell degranulation in clinic [18]. Although some migraine rats in the model group showed some complications such as burnout behavior at the end of the experiment, this model was preferred compared to other migraine rat models because of the other rat migraine models [42, 43] require invasive manipulation of the rat head, which can affect the MRI scan. Therefore, in order to obtain a more stable and undisturbed spectrum, we chose GTN for migraine induction.

The behavioral manifestations of migraine model induced by nitroglycerin were mostly as follows: allodynia [44] and hyperalgesia [45]. Allodynia test include heat sensitivity and Mechanical nociceptive thresholds, both are hurtful stimuli. GTN-induced hyperalgesia included the tail flick test and the formalin test, which is also the hurtful stimuli. These behavioral tests affect the purpose of the experiment. For another, the spontaneous behavior of headache induced by GTN was unstable. Although light sensitivity changes before and after the model, it does not have repeatability. Burrowing behavior, running wheel activity and light sensitivity cannot be used to establish successful behavioral criteria for GTN mode [46]. Recent studies have shown that reflex blink-associated EMG response [47] can be used as a successful evaluation criterion for 2 h modeling of migraine induced by GTN, but this test requires anesthesia rather than wakefulness, so it is not suitable for this study.

留言 (0)

沒有登入
gif