Critical role of calcitonin gene-related peptide 1 receptors in the amygdala in synaptic plasticity and pain behavior
Critical role of calcitonin gene-related peptide 1 receptors in the amygdala in synaptic plasticity and pain behavior
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DOI：
10.1523/jneurosci.4112-05.2005
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发表时间：
2005-11-16
影响因子：
5.3
通讯作者：
Neugebauer, V
中科院分区：
文献类型：
--
作者：
Han, JS;Li, WD;Neugebauer, V
神经肽在突触可塑性中的作用不如谷氨酸等经典递质那么清楚。在这里，我们报告的重要性，G蛋白偶联降钙素基因相关肽（CGRP 1）受体作为杏仁核可塑性和疼痛行为之间的关键环节。杏仁核是情绪性和情感障碍的关键参与者，它与疼痛和情感之间的关系有很好的记录，但机制上无法解释。我们的电生理学和药理学体外（膜片钳记录）和体内（细胞外单单位记录）数据显示，选择性CGRP 1受体拮抗剂（CGRP 8 -37和BIBN 4096 BS）在杏仁核逆转关节炎疼痛相关的可塑性通过蛋白激酶A（PKA）依赖性突触后机制，涉及NMDA受体。与正常对照组相比，CGRP 1受体拮抗剂抑制关节炎大鼠脑片杏仁核中央核（CeLC）外侧囊区的突触可塑性。这种效应伴随着神经元兴奋性降低和微型EPSC的振幅降低，但频率不降低;成对脉冲易化不受影响。PKA抑制剂阻断了拮抗剂的作用。CGRP 1受体阻断剂也直接抑制NMDA诱发的膜电流，但不抑制AMPA诱发的膜电流。总之，这些数据表明了突触后的作用部位。在系统水平上，拮抗剂逆转了关节炎疼痛模型中麻醉大鼠中伤害感受性CeLC神经元的敏化。重要的是，在CeLC中的CGRP 1受体阻断剂抑制清醒的关节炎大鼠的脊髓（后肢退缩反射）和脊髓上疼痛行为，包括情感反应，如超声波发声。本研究为疼痛行为对CGRP 1介导的杏仁核可塑性的关键依赖性提供了直接证据。
The role of neuropeptides in synaptic plasticity is less well understood than that of classical transmitters such as glutamate. Here we report the importance of the G-protein-coupled calcitonin gene-related peptide (CGRP1) receptor as a critical link between amygdala plasticity and pain behavior. A key player in emotionality and affective disorders, the amygdala has been implicated in the well documented, but mechanistically unexplained, relationship between pain and affect. Our electrophysiological and pharmacological in vitro (patch-clamp recordings) and in vivo (extracellular single-unit recordings) data show that selective CGRP1 receptor antagonists (CGRP8-37 and BIBN4096BS) in the amygdala reverse arthritis pain-related plasticity through a protein kinase A (PKA)-dependent postsynaptic mechanism that involves NMDA receptors. CGRP1 receptor antagonists inhibited synaptic plasticity in the laterocapsular division of the central nucleus of the amygdala (CeLC) in brain slices from arthritic rats compared with normal controls. The effects were accompanied by decreased neuronal excitability and reduced amplitude, but not frequency, of miniature EPSCs; paired-pulse facilitation was unaffected. The antagonist effects were occluded by a PKA inhibitor. CGRP1 receptor blockade also directly inhibited NMDA-evoked, but not AMPA-evoked, membrane currents. Together, these data suggest a postsynaptic site of action. At the systems level, the antagonists reversed the sensitization of nociceptive CeLC neurons in anesthetized rats in the arthritis pain model. Importantly, CGRP1 receptor blockade in the CeLC inhibited spinal (hindlimb withdrawal reflexes) and supraspinal pain behavior of awake arthritic rats, including affective responses such as ultrasonic vocalizations. This study provides direct evidence for the critical dependence of pain behavior on CGRP1-mediated amygdala plasticity.