Deficiency in the function of inhibitory interneurons contributes to glutamate‐associated central sensitization through GABABR2‐SynCAM1 signaling in chronic migraine rats
Deficiency in the function of inhibitory interneurons contributes to glutamate‐associated central sensitization through GABABR2‐SynCAM1 signaling in chronic migraine rats
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DOI：
10.1096/fj.202001561r
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发表时间：
2020-09
期刊：
影响因子：
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通讯作者：
Xiaoxu Zeng;Y. Niu;Guangcheng Qin;Dunke Zhang;Jiying Zhou;Lixue Chen
中科院分区：
文献类型：
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作者：
Xiaoxu Zeng;Y. Niu;Guangcheng Qin;Dunke Zhang;Jiying Zhou;Lixue Chen
疼痛的发生一直与兴奋性和抑制性系统之间平衡的打破密切相关，而在慢性偏头痛（CM）的发病机制中，这两个系统之间的内在关系尚未得到研究。在这项研究中，我们探讨了抑制性中间神经元如何特异性地调节CM大鼠中脑导水管周围灰质（PAG）中谷氨酸诱导的过度兴奋。采用反复硬膜外注入炎症汤（IS）的方法建立CM模型。然后，通过脑室内注射巴氯芬（一种γ-氨基丁酸型B受体（GABABR）激动剂）、CGP 35348（一种GABABR拮抗剂）、H89（一种蛋白激酶A（PKA）抑制剂）和8-溴-cAMP（一种PKA激动剂）来研究CM的详细机制。结果表明，CM大鼠PAG中GABABR 2 mRNA和蛋白水平均显著下调（P <0.01）。同样，γ-氨基丁酸（GABA）及其合成酶谷氨酸脱羧酶65/67（GAD 65/67）严重降低（P <0.01），这意味着CM大鼠PAG中抑制性中间神经元的功能缺陷。随后，巴氯芬和H89的应用通过调节CM大鼠PAG中的GABABR 2/PKA/SynCAM 1通路减轻了IS诱发的痛觉过敏并减少了囊泡谷氨酸转运体2（VGLUT 2）、谷氨酸、降钙素基因相关肽（CGRP）和c-Fos的表达，而CGP 35348和8-Bromo-cAMP的应用恰好发挥了相反的作用。重要的是，CGP 35348诱导CGRP升高，H89缓解VGLUT 2表达。这些数据表明，抑制性中间神经元功能的丧失通过CM大鼠PAG中的GABABR 2/PKA/SynCAM 1通路促进谷氨酸相关的中枢敏化。
The occurrence of pain has always been closely related to a break in the balance between excitatory and inhibitory systems, and the internal relationship between these two systems has not been studied in the pathogenesis of chronic migraine (CM). In this study, we explored how inhibitory interneurons specifically modulate the glutamate‐induced hyperexcitability in the periaqueductal gray (PAG) of CM rats. The CM model was established by repeated dural infusion of inflammatory soup (IS) in rats. Then, Baclofen, a gamma‐aminobutyric acid type B receptor (GABABR) agonist; CGP35348, a GABABR antagonist; H89, a protein kinase A (PKA) inhibitor; and 8‐Bromo‐cAMP, a PKA agonist, were applied by intraventricular injection to investigate the detailed CM mechanism. Our results showed that GABABR2 mRNA and protein levels were significantly downregulated (P < .01) in the PAG of CM rats. Similarly, gamma‐aminobutyric acid (GABA) and its synthetase glutamate decarboxylase 65/67 (GAD65/67) seriously decreased (P < .01), implying a deficit in the function of inhibitory interneurons in the PAG of CM rats. Afterward, the application of Baclofen and H89 alleviated the IS‐evoked hyperalgesia and extenuated vesicular glutamate transporter 2 (VGLUT2), glutamate, calcitonin gene‐related peptide (CGRP), and c‐Fos expression by regulating the GABABR2/PKA/SynCAM1 pathway in the PAG of CM rats, while the application of CGP35348 and 8‐Bromo‐cAMP exactly exerted the opposite effect. Importantly, CGP35348 induced an elevation of CGRP, and VGLUT2 expression was relieved by H89. These data suggest that the loss in the function of inhibitory interneurons contributes to glutamate‐associated central sensitization through the GABABR2/PKA/SynCAM1 pathway in the PAG of CM rats.