Phosphoproteomics and bioinformatics analyses of spinal cord proteins in rats with morphine tolerance.
Phosphoproteomics and bioinformatics analyses of spinal cord proteins in rats with morphine tolerance.
复制标题
具有吗啡耐受性大鼠的脊髓蛋白的磷酸蛋白质组学和生物信息学分析。
DOI：
10.1371/journal.pone.0083817
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Shui HA
中科院分区：
文献类型：
--
作者：
Liaw WJ;Tsao CM;Huang GS;Wu CC;Ho ST;Wang JJ;Tao YX;Shui HA
吗啡是最有效的止痛药，但它会引起不受欢迎的副作用。脊髓内直接给予吗啡不仅可以有效、可靠地缓解疼痛，而且还可以防止脊髓上副作用的发生。然而，反复给药仍有可能导致吗啡耐受。为了更好地了解吗啡耐受的机制，我们在脊髓水平通过每天两次注射吗啡(20微克/10微克L)连续4天来诱导大鼠对吗啡的耐受。我们在第5天通过测量爪子的缩足潜伏期和吗啡的最大可能的镇痛作用来确认耐受性。然后，我们进行了磷酸蛋白质组学分析，以研究与吗啡耐受性相关的脊髓蛋白的整体磷酸化。最后，通过下拉实验确定14-3-3蛋白的磷酸化类型和位置，并应用生物信息学预测受吗啡调节的蛋白影响的生物网络。我们的蛋白质组学数据显示，重复的吗啡治疗改变了脊髓中10种蛋白质的磷酸化。下拉实验确定了14-3-3蛋白中的2个丝氨酸/苏氨酸磷酸化位点。生物信息学进一步揭示了吗啡对细胞骨架重组、神经可塑性、蛋白质折叠和调制、信号转导和生物分子代谢的影响。重复使用吗啡可能通过改变蛋白质的磷酸化作用而影响多个生物网络。这些数据可能为了解吗啡耐受形成的机制提供依据。
Morphine is the most effective pain-relieving drug, but it can cause unwanted side effects. Direct neuraxial administration of morphine to spinal cord not only can provide effective, reliable pain relief but also can prevent the development of supraspinal side effects. However, repeated neuraxial administration of morphine may still lead to morphine tolerance. To better understand the mechanism that causes morphine tolerance, we induced tolerance in rats at the spinal cord level by giving them twice-daily injections of morphine (20 µg/10 µL) for 4 days. We confirmed tolerance by measuring paw withdrawal latencies and maximal possible analgesic effect of morphine on day 5. We then carried out phosphoproteomic analysis to investigate the global phosphorylation of spinal proteins associated with morphine tolerance. Finally, pull-down assays were used to identify phosphorylated types and sites of 14-3-3 proteins, and bioinformatics was applied to predict biological networks impacted by the morphine-regulated proteins. Our proteomics data showed that repeated morphine treatment altered phosphorylation of 10 proteins in the spinal cord. Pull-down assays identified 2 serine/threonine phosphorylated sites in 14-3-3 proteins. Bioinformatics further revealed that morphine impacted on cytoskeletal reorganization, neuroplasticity, protein folding and modulation, signal transduction and biomolecular metabolism. Repeated morphine administration may affect multiple biological networks by altering protein phosphorylation. These data may provide insight into the mechanism that underlies the development of morphine tolerance.
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影响因子：
14.9
作者：
Jensen LJ;Kuhn M;Stark M;Chaffron S;Creevey C;Muller J;Doerks T;Julien P;Roth A;Simonovic M;Bork P;von Mering C
通讯作者：
von Mering C
影响因子：
5.3
作者：
Dobashi T;Tanabe S;Jin H;Mimura N;Yamamoto T;Nishino T;Aoe T
通讯作者：
Aoe T
影响因子：
2.5
作者：
Alonso, Elba;Garrido, Elisa;Alguacil, Luis F.
通讯作者：
Alguacil, Luis F.
DOI：
10.1016/s1521-6896(03)00014-4
发表时间：
2003-09-01
期刊：
Best practice & research. Clinical anaesthesiology
影响因子：
--
作者：
Gerber, Helmut R
通讯作者：
Gerber, Helmut R
影响因子：
7
作者：
Larsen, MR;Thingholm, TE;Jorgensen, TJD
通讯作者：
Jorgensen, TJD