Disrupting interaction of PSD-95 with nNOS attenuates hemorrhage-induced thalamic pain.
Disrupting interaction of PSD-95 with nNOS attenuates hemorrhage-induced thalamic pain.
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DOI：
10.1016/j.neuropharm.2018.09.003
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发表时间：
2018-10
影响因子：
4.7
通讯作者：
Tao YX
中科院分区：
文献类型：
--
作者：
Cai W;Wu S;Pan Z;Xiao J;Li F;Cao J;Zang W;Tao YX
丘脑出血会导致疼痛综合症。丘脑痛的临床治疗是无效的，至少在一定程度上，由于丘脑痛的诱发和维持机制难以捉摸。本研究探讨了突触后密度蛋白95 （PSD-95）和神经元一氧化氮合酶（nNOS）之间的蛋白-蛋白相互作用对小鼠丘脑疼痛的可能贡献。将IV型胶原酶微量注入丘脑单侧腹侧后内侧/外侧核，诱导丘脑出血。对侧疼痛超敏反应，包括机械异常痛觉、热痛觉和冷异常痛觉，在微注射后第1天出现，在微注射后5-7天达到高峰，并在微注射后持续至少28天。ZL006是一种破坏PSD-95-nNOS相互作用的小分子，系统的预处理（而不是后处理）减轻了这些疼痛超敏反应。这种效应是剂量依赖性的。在机制上，ZL006阻断了出血诱导的PSD-95与丘脑神经元nNOS结合的增加和nNOS的膜移位。我们的研究结果表明，PSD-95和丘脑nNOS之间的蛋白-蛋白相互作用在丘脑疼痛的诱导中起着重要作用。这种相互作用可能是出血性丘脑痛临床治疗中有希望的治疗靶点。
Hemorrhages occurring within the thalamus lead to a pain syndrome. Clinical treatment of thalamic pain is ineffective, at least in part, due to the elusive mechanisms that underlie the induction and maintenance of thalamic pain. The present study investigated the possible contribution of a protein-protein interaction between postsynaptic density protein 95 (PSD-95) and neuronal nitric oxide synthase (nNOS) to thalamic pain in mice. Thalamic hemorrhage was induced by microinjection of type IV collagenase into unilateral ventral posterior medial/lateral nuclei of the thalamus. Pain hypersensitivities, including mechanical allodynia, heat hyperalgesia , and cold allodynia, appeared at day 1 post-microinjection, reached a peak 5–7 days post-microinjection, and persisted for at least 28 days post-microinjection on the contralateral side. Systemic pre-treatment (but not post-treatment) of ZL006, a small molecule that disrupts PSD-95-nNOS interaction, alleviated these pain hypersensitivities. This effect is dose-dependent. Mechanistically, ZL006 blocked the hemorrhage-induced increase of binding of PSD-95 with nNOS and membrane translocation of nNOS in thalamic neurons. Our findings suggest that the protein-protein interaction between PSD-95 and nNOS in the thalamus plays a significant role in the induction of thalamic pain. This interaction may be a promising therapeutic target in the clinical management of hemorrhage-induced thalamic pain.
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影响因子：
7.3
作者：
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通讯作者：
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影响因子：
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影响因子：
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