Caveolin-1 in the Anterior Cingulate Cortex Modulates Chronic Neuropathic Pain via Regulation of NMDA Receptor 2B Subunit
Caveolin-1 in the Anterior Cingulate Cortex Modulates Chronic Neuropathic Pain via Regulation of NMDA Receptor 2B Subunit
复制标题
前扣带皮层中的 Caveolin-1 通过调节 NMDA 受体 2B 亚基调节慢性神经病理性疼痛
DOI：
10.1523/jneurosci.1161-14.2015
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发表时间：
2015-01-07
影响因子：
5.3
通讯作者：
Cao, Jun-Li
中科院分区：
文献类型：
--
作者：
Yang, Jun-Xia;Hua, Lu;Cao, Jun-Li
慢性疼痛仍然是一个基础科学和临床挑战。揭示慢性疼痛涉及的神经生物学机制将为治疗策略的开发提供新的靶点。众所周知，前扣带皮层 (ACC) 的中枢敏化在慢性疼痛的发生、发展和维持中起着至关重要的作用。然而，潜在的机制仍然难以捉摸。在这里，我们报道了小鼠慢性缩窄性损伤（CCI）后，膜筏中的一种支架蛋白 Caveolin-1 (Cav-1) 在 ACC 神经元中持续上调和激活。敲低或阻断损伤侧对侧 ACC 中的 Cav-1 可逆转 CCI 诱导的疼痛行为和神经元敏化，以及在未受影响的后爪中同侧 ACC 诱导的疼痛行为中 Cav-1 的过度表达。此外，我们发现 Cav-1 直接与 NMDA 受体 2B 亚基 (NR2B) 结合并提高 ACC 中 NR2B 表面水平有助于调节慢性神经性疼痛。通过将源自 NR2B C 末端的短肽显微注射到 ACC 中，破坏 Cav-1 和 NR2B 的相互作用，表现出与表面 NR2B 表达减少相关的显着抗伤害作用。此外，Cav-1 增加细胞内 Ca2+ 浓度，并在 ACC 中以 NR2B 依赖性方式激活 ERK/CREB 信号通路。我们的研究结果表明，ACC 神经元中的 Cav-1 通过调节 NR2B 和随后激活 ERK/CREB 信号传导来调节慢性神经性疼痛，这表明可能有小窝蛋白介导的过程参与与疼痛调节有关的神经元传递途径。
Chronic pain is still a basic science and clinical challenge. Unraveling of the neurobiological mechanisms involved in chronic pain will offer novel targets for the development of therapeutic strategies. It is well known that central sensitization in the anterior cingulate cortex (ACC) plays a critical role in initiation, development, and maintenance of chronic pain. However, the underlying mechanisms still remain elusive. Here, we reported that caveolin-1 (Cav-1), a scaffolding protein in membrane rafts, was persistently upregulated and activated in the ACC neurons after chronic constriction injury (CCI) in mice. Knockdown or blocking of Cav-1 in the contralateral ACC to the injury side reversed CCI-induced pain behavioral and neuronal sensitization and overexpression of Cav-1 in the ipsilateral ACC-induced pain behavior in the unaffected hindpaw. Furthermore, we found that Cav-1 directly binding with NMDA receptor 2B subunit (NR2B) and promotion of NR2B surface levels in the ACC contributed to modulation of chronic neuropathic pain. Disrupting the interaction of Cav-1 and NR2B through microinjection of a short peptide derived from the C-terminal of NR2B into the ACC exhibited a significant anti-nociception effect associated with decrease of surface NR2B expression. Moreover, Cav-1 increased intracellular Ca2+ concentration and activated the ERK/CREB signaling pathway in an NR2B-dependent manner in the ACC. Our findings implicate that Cav-1 in the ACC neurons modulates chronic neuropathic pain via regulation of NR2B and subsequent activation of ERK/ CREB signaling, suggesting a possible caveolin-mediated process would participate in neuronal transmission pathways implicated in pain modulation.