Carrageenan induced phosphorylation of Akt is dependent on neurokinin-1 expressing neurons in the superficial dorsal horn.
Carrageenan induced phosphorylation of Akt is dependent on neurokinin-1 expressing neurons in the superficial dorsal horn.
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DOI：
10.1186/1744-8069-8-4
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发表时间：
2012-01-13
期刊：
影响因子：
3.3
通讯作者：
Sorkin LS
中科院分区：
文献类型：
--
作者：
Choi JI;Koehrn FJ;Sorkin LS
角叉菜胶诱导背角神经元中磷脂酰肌醇3-激酶（PI-3 K）和Akt的活化，以及疼痛行为的诱导。脊髓PI-3 K活化也被认为是炎症诱导的GluA 1（AMPA受体亚单位）从胞质溶胶运输到质膜所需的。Akt的磷酸化具有独特的时间过程。它首先发生在浅表背角（0.75小时），然后很快消散，一个小时后由Akt磷酸化在更深的背角板层，主要是板V。最初，我们希望确定Akt磷酸化在更深的板层依赖于板I，神经激肽受体的存在下，轴承投射神经元。随着研究的进展，我们的目标越来越多地包括这个问题，角叉菜胶诱导的GluA 1亚基运输是否是Akt磷酸化的下游。用与稳定形式的P物质结合的脊髓皂草素预处理的大鼠在其整个表面但不是深背角中具有神经激肽1受体的神经元大量损失。与单独用脊髓皂草素预处理的动物相比，用物质P-皂草素预处理的动物表现出运动能力没有变化，并且角叉菜胶诱导的机械性异常性疼痛小但显著降低。重要的是，角叉菜胶诱导的Akt磷酸化被阻断，在物质P-皂草素治疗组，在整个脊髓灰质。与此形成鲜明对比的是，角叉菜胶诱导的运输的GluA 1受体亚基增加相等的两个治疗组。我们从这些数据推断：1）深背角中Akt的磷酸化依赖于浅背角中携带NK 1受体的细胞的先前活化，以及2）存在由PI-3 K活化下游的角叉菜胶注射引发的平行脊髓细胞内级联，包括一个含有Akt的级联和另一个涉及GluA 1运输到神经元质膜中的级联，其分别导致增强的疼痛行为。这些结果意味着PI-3 K下游的两条通路可以被单独激活，因此应该能够被独立抑制。
Paw carrageenan induces activation of phosphatidylinositol 3-kinase (PI-3K) and Akt in dorsal horn neurons in addition to induction of pain behavior. Spinal PI-3K activation is also thought to be required for inflammation-induced trafficking of GluA1, AMPA receptor subunits, into plasma membranes from cytosol. Phosphorylation of Akt has a unique time course. It occurs first in the superficial dorsal horn (0.75 h), then soon dissipates and is followed an hour later by Akt phosphorylation in deeper dorsal horn laminae, primarily lamina V. Initially, we wished to determine if Akt phosphorylation in the deeper laminae were dependent on the presence of lamina I, neurokinin receptor bearing projection neurons. As the study progressed, our aims grew to include the question, whether carrageenan-induced GluA1 subunit trafficking was downstream of Akt phosphorylation. Rats pretreated with spinal saporin conjugated to a stabilized form of substance P had substantial loss of neurons with neurokinin 1 receptors throughout their superficial, but not deep dorsal horns. Animals pre-treated with substance P-saporin exhibited no change in locomotor ability and a small, but significant decrease in carrageenan-induced mechanical allodynia when compared to animals pre-treated with spinal saporin alone. Importantly, carrageenan-induced phosphorylation of Akt was blocked, in the substance P-saporin treated group, throughout the spinal cord grey matter. In marked contrast, carrageenan induced-trafficking of the GluA1 receptor subunit increased equivalently in both treatment groups. We infer from these data that 1) phosphorylation of Akt in the deep dorsal horn is dependent on prior activation of NK1 receptor bearing cells in superficial dorsal horn, and 2) there are parallel spinal intracellular cascades initiated by the carrageenan injection downstream of PI-3K activation, including one containing Akt and another involving GluA1 trafficking into neuronal plasma membranes that separately lead to enhanced pain behavior. These results imply that the two pathways downstream of PI-3K can be activated separately and therefore should be able to be inhibited independently.
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