5-HT2 receptor activation facilitates a persistent sodium current and repetitive firing in spinal motoneurons of rats with and without chronic spinal cord injury
5-HT2 receptor activation facilitates a persistent sodium current and repetitive firing in spinal motoneurons of rats with and without chronic spinal cord injury
复制标题
DOI：
10.1152/jn.01088.2005
复制
发表时间：
2006-09-01
影响因子：
2.5
通讯作者：
Bennett, D. J.
中科院分区：
文献类型：
--
作者：
Harvey, P. J.;Li, X.;Bennett, D. J.
本研究观察了正常和慢性脊髓损伤大鼠脊髓运动神经元5-羟色胺（5-HT）对持续性内向电流（PIC）的调制作用。PIC由TTX敏感的持续性钠电流（Na PIC）和尼莫地平敏感的持续性钙电流（Ca PIC）组成，我们专注于定量Na PIC（及其对总PIC的作用），已知其在实现重复放电中至关重要。在S2脊髓水平（急性脊髓大鼠条件）急性横断脊髓后，从动物中取出，然后保持在体外，从正常成年大鼠的整个骶尾脊髓的运动神经元进行细胞内记录。体外运动神经元记录同样来自于2个月前进行骶脊髓横断的大鼠（慢性脊髓大鼠）。在急性脊髓损伤大鼠的运动神经元中，中等剂量的5-HT（>= 10 μ M）或5-HT 2受体激动剂DOI（>= 30 μ M）显著增加总PIC，使PIC起始电压超极化，并使峰电位阈值超极化，而较低剂量则无影响。5-HT和DOI均特异性增加总PIC的Na PIC部分（用尼莫地平阻断Ca PIC测试）。此外，5-HT，而不是DOI，去极化静息膜电位（V-m）和增加输入电阻（R-m）的剂量依赖性方式。因此，5-HT_2受体激活促进Na PIC，而其它5-HT受体调节V-m和R-m。慢性脊髓大鼠运动神经元对5-HT和DOI的反应方式相同，但反应更大，剂量低得多（0.3-1 μ M），因此表现出30倍的超敏感性5-HT。具体地说，Na PIC对DOI激活的5-HT 2受体超敏感。Rm和Vm对5-HT超敏感。与已知的钠PIC在重复放电中的关键作用一致，DOI或5-HT促进了钠PIC的增强，促进了稳定电流注射诱发的重复放电，并使急性脊髓大鼠运动神经元亚群中的重复放电最初无法产生持续的重复放电。我们认为，脊髓横断后，残留的内源性5-HT脊髓来源有助于促进钠PIC和重复放电。在慢性损伤时，发展的5-HT超敏感性超过了对脑干5-HT损失的补偿，使得Na PIC大，运动神经元非常兴奋，从而导致痉挛。
We examined the modulation of persistent inward currents (PICs) by serotonin (5-HT) in spinal motoneurons of normal and chronic spinal rats. PICs are composed of both a TTX-sensitive persistent sodium current (Na PIC) and a nimodipine-sensitive persistent calcium current (Ca PIC), and we focused on quantifying the Na PIC ( and its action on the total PIC), which is known to be critical in enabling repetitive firing. Intracellular recordings were made from motoneurons of the whole sacrocaudal spinal cord of normal adult rats after the cord was acutely transected at the S2 spinal level (acute spinal rat condition), removed from the animal, and then maintained in vitro. In vitro motoneuron recordings were likewise made from rats that had a sacral spinal transection 2 mo previously (chronic spinal rats). In motoneurons from acute spinal rats, moderately high doses of 5-HT (>= 10 mu M), or the 5-HT2 receptor agonist DOI (>= 30 mu M), significantly increased the total PIC, hyperpolarized the PIC onset voltage, and hyperpolarized the spike threshold, whereas lower doses had no effect. Both 5-HT and DOI specifically increased the Na PIC portion of the total PIC (tested with nimodipine blocking the Ca PIC). Additionally, 5-HT, but not DOI, depolarized the resting membrane potential (V-m) and increased the input resistance (R-m) in a dose-dependent manner. Therefore 5-HT2 receptor activation facilitated the Na PIC, whereas other 5-HT receptors modulated V-m and R-m. Motoneurons of chronic spinal rats responded to 5-HT and DOI in the same way, but with larger responses and at much lower doses (0.3-1 mu M), thus exhibiting a 30-fold supersensitivity to 5-HT. Specifically the Na PIC was supersensitive to 5-HT2 receptor activation with DOI. Also, R m and V m were supersensitive to 5-HT. Consistent with the known critical role of the Na PIC in repetitive firing, enhancement of the Na PIC by DOI or 5-HT facilitated the repetitive firing evoked by steady current injection and enabled repetitive firing in a subpopulation of motoneurons of acute spinal rats that were initially unable to produce sustained repetitive firing. We suggest that after spinal transection, residual endogenous spinal sources of 5-HT help facilitate the Na PIC and repetitive firing. With chronic injury, the developed 5-HT supersensitivity more than compensates for lost brain stem 5-HT, so that the Na PIC is large and motoneurons are very excitable, thus contributing to spasticity.