Is endogenous D-serine in the rostral anterior cingulate cortex necessary for pain-related negative affect?
Is endogenous D-serine in the rostral anterior cingulate cortex necessary for pain-related negative affect?
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DOI：
10.1111/j.1471-4159.2006.03677.x
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发表时间：
2006-03-01
影响因子：
4.7
通讯作者：
Zhang, YQ
中科院分区：
文献类型：
--
作者：
Ren, WH;Guo, JD;Zhang, YQ
NMDA受体的功能激活需要谷氨酸和甘氨酸结合位点的共同激活。d -丝氨酸被认为是NMDA受体甘氨酸位点的内源性配体。利用大鼠福尔马林诱导的条件性场所回避（F-CPA）行为模型和吻侧前扣带皮层（rACC）切片的全细胞膜片钳记录，我们研究了d -氨基酸氧化酶（DAAO）（一种内源性d -丝氨酸降解酶）和7-氯代尿酸（7Cl-KYNA）（一种NMDA受体甘氨酸位点的拮抗剂）对疼痛相关厌恶的影响。DAAO降解内源性d -丝氨酸，或7Cl-KYNA选择性阻断NMDA受体甘氨酸位点，可有效抑制rACC切片中NMDA诱发电流。在F-CPA条件反射前20分钟，racc内注射DAAO （0.1 U）和7Cl-KYNA（2和0.2 mM\，每侧0.6 μ L）显著降低了F-CPA评分，但对福尔马林诱导的急性伤害性行为和电足电击诱导的条件性场所回避没有影响。本研究首次揭示了内源性d -丝氨酸通过激活rACC中NMDA受体的甘氨酸位点在疼痛相关厌恶中起关键作用。此外，这些结果扩展了我们的假设，即rACC中NMDA受体的激活对于特定疼痛相关负面情绪的获得是必要的。由此提出了一种预防慢性疼痛引起的情绪障碍的新策略。
Functional activation of NMDA receptors requires co-activation of glutamate- and glycine-binding sites. D-serine is considered to be an endogenous ligand for the glycine site of NMDA receptors. Using a combination of a rat formalin-induced conditioned place avoidance (F-CPA) behavioral model and whole-cell patch-clamp recording in rostral anterior cingulate cortex (rACC) slices, we examined the effects of D-amino acid oxidase (DAAO), an endogenous D-serine-degrading enzyme, and 7-chlorokynurenate (7Cl-KYNA), an antagonist of the glycine site of NMDA receptors, on pain-related aversion. Degradation of endogenous D-serine with DAAO, or selective blockade of the glycine site of NMDA receptors by 7Cl-KYNA, effectively inhibited NMDA-evoked currents in rACC slices. Intra-rACC injection of DAAO (0.1 U) and 7Cl-KYNA (2 and 0.2 mM\, 0.6 mu L per side) 20 min before F-CPA conditioning greatly attenuated F-CPA scores, but did not affect formalin-induced acute nociceptive behaviors and electric foot shock-induced conditioned place avoidance. This study reveals for the first time that endogenous D-serine plays a critical role in pain-related aversion by activating the glycine site of NMDA receptors in the rACC. Furthermore, these results extend our hypothesis that activation of NMDA receptors in the rACC is necessary for the acquisition of specific pain-related negative emotion. Thus a new and promising strategy for the prevention of chronic pain-induced emotional disturbance might be raised.