Blocking Palmitoylation of Apelin Receptor Alleviates Morphine Tolerance in Neuropathic Cancer Pain.
Blocking Palmitoylation of Apelin Receptor Alleviates Morphine Tolerance in Neuropathic Cancer Pain.
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DOI：
10.7150/ijbs.86888
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发表时间：
2024
影响因子：
9.2
通讯作者：
Fang Z
中科院分区：
文献类型：
--
作者：
Fan X;Gong M;Zhang S;Niu W;Sun S;Yu H;Chen X;Fang Z
神经病理性癌痛(NCP)是癌症患者的重要症状。然而，显著的止痛耐受性和其他副作用严重阻碍了吗啡的使用。DHHC家族介导的蛋白棕榈酰化可能参与了器官衰竭引起的神经胶质细胞活化和炎症反应。在这项研究中，我们研究了蛋白质棕榈酰化在癌症疼痛中的关键作用，并试图以棕榈酰化为靶点来抑制吗啡耐受。我们发现长期使用吗啡导致吗啡代谢产物吗啡-3-葡萄糖醛酸苷在体内蓄积，并通过APLNR激活ERK1/2和小胶质细胞释放炎症因子。棕榈酰转移酶ZDHHC9在NCP中表达上调，APLNR被棕榈化以保护其免受溶酶体降解并保持其稳定性。我们还设计了APLNR棕榈酰化的竞争性抑制剂，以抑制NCP的发展，炎症因子的释放，以及吗啡耐受性的减弱。因此，靶向APLNR棕榈酰化联合吗啡是治疗癌痛的有效方法。我们的数据为未来相关药物联合吗啡治疗癌症相关疼痛提供了依据。
Neuropathic cancer pain (NCP) is an important symptom in patients with cancer. However, significant analgesic tolerance and other side effects critically hamper the administration of morphine. Protein palmitoylation mediated by the DHHC family may be involved in the glial activation and inflammatory responses underlying organ failure. In this study, we investigated the key role of protein palmitoylation in cancer pain and sought to target palmitoylation to suppress morphine tolerance. We found that long-term use of morphine led to the accumulation of the morphine metabolite, morphine-3-glucuronide, in vivo and activated ERK1/2 and microglia to release inflammatory factors through the apelin receptor APLNR. Palmitoyltransferase ZDHHC9 was upregulated in NCP, and APLNR was palmitylated to protect it from lysosomal degradation and to maintain its stability. We also designed competitive inhibitors of APLNR palmitoylation to inhibit the development of NCP, release of inflammatory factors, and attenuation of morphine tolerance. Therefore, targeting APLNR palmitoylation in combination with morphine is a potent method for cancer pain treatment. Our data provide a basis for the future clinical use of related drugs combined with morphine for the treatment of cancer-related pain.
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影响因子：
4.8
作者：
Pan, Yanling;Xiao, Yucheng;Cummins, Theodore R.
通讯作者：
Cummins, Theodore R.
神经性疼痛背后的神经免疫机制：TNF-α-坏死性凋亡途径的潜在作用
影响因子：
5.6
作者：
Duan, Yi-Wen;Chen, Shao-Xia;Li, Qiao-Yun;Zang, Ying
通讯作者：
Zang, Ying
影响因子：
7.4
作者：
Raghavendra, V;Tanga, F;DeLeo, JA
通讯作者：
DeLeo, JA
DOI：
10.1186/1756-9966-28-61
发表时间：
2009-05-07
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Aurilio C;Pace MC;Pota V;Sansone P;Barbarisi M;Grella E;Passavanti MB
通讯作者：
Passavanti MB
神经炎症驱动的慢性疼痛的新兴目标。
影响因子：
120.1
作者：
Ji, Ru-Rong;Xu, Zhen-Zhong;Gao, Yong-Jing
通讯作者：
Gao, Yong-Jing