Accessibility of axonal G protein coupled mu‐opioid receptors requires conceptual changes of axonal membrane targeting for pain modulation
Accessibility of axonal G protein coupled mu‐opioid receptors requires conceptual changes of axonal membrane targeting for pain modulation
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DOI：
10.1016/j.jconrel.2017.10.016
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发表时间：
2017-12
影响因子：
10.8
通讯作者：
S. Mousa;M. Shaqura;Mohammed A Al-Madol;S. Tafelski;Baled I. Khalefa;M. Shakibaei;M. Schäfer
中科院分区：
文献类型：
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作者：
S. Mousa;M. Shaqura;Mohammed A Al-Madol;S. Tafelski;Baled I. Khalefa;M. Shakibaei;M. Schäfer
钠通道的轴突运输和膜靶向机制已得到很好的确立，这是神经周围应用局部麻醉剂的主要靶点。然而，尚未对G蛋白偶联受体如μ-阿片受体（莫尔）进行彻底研究。聚焦于这些轴突机制，我们发现轴突莫尔功能在两种不同的疼痛状态中是相当不同的，即后爪炎症和神经损伤。我们观察到轴突膜莫尔结合和功能性G蛋白偶联仅在CCI神经损伤部位。此外，在这些轴突膜位点，莫尔表现出与膜蛋白SNAP和Na/K-ATP酶以及NGF依赖性增强脂筏和L1 CAM锚定蛋白的广泛共定位。用鞘内L1 CAM特异性siRNA沉默内源性L1 CAM，用神经束膜胆固醇螯合剂MβCD破坏脂筏，以及用神经束膜NGF受体抑制剂K252 a抑制NGF受体活化，消除了莫尔轴突膜整合、功能偶联和激动剂引起的神经损伤部位的抗伤害感受。这些结果表明，局部概念的变化，神经损伤所造成的功能轴突膜莫尔的建立。轴突整合和随后的功能性偶联的莫尔的可及性具有很大的相关性，特别是对于由于神经损伤或肿瘤浸润而遭受严重疼痛的患者。
The mechanisms of axonal trafficking and membrane targeting are well established for sodium channels, which are the principle targets for perineurally applied local anaesthetics. However, they have not been thoroughly investigated for G protein coupled receptors such as mu-opioid receptors (MOR). Focusing on these axonal mechanisms, we found that axonal MOR functionality is quite distinct in two different pain states, i.e. hindpaw inflammation and nerve injury. We observed axonal membrane MOR binding and functional G protein coupling exclusively at sites of CCI nerve injury. Moreover at these axonal membrane sites, MOR exhibited extensive co-localization with the membrane proteins SNAP and Na/K-ATPase as well as NGF-dependent enhanced lipid rafts and L1CAM anchoring proteins. Silencing endogenous L1CAM with intrathecal L1CAM specific siRNA, disrupting lipid rafts with the perineurial cholesterol-sequestering agent MβCD, as well as suppressing NGF receptor activation with the perineurial NGF receptor inhibitor K252a abrogated MOR axonal membrane integration, functional coupling, and agonist-elicited antinociception at sites of nerve injury. These findings suggest that local conceptual changes resulting from nerve injury are required for the establishment of functional axonal membrane MOR. Axonal integration and subsequent accessibility of functionally coupled MOR are of great relevance particularly for patients suffering from severe pain due to nerve injury or tumour infiltration.