Endogenous monoamine receptor activation is essential for enabling persistent sodium currents and repetitive firing in rat spinal motoneurons
Endogenous monoamine receptor activation is essential for enabling persistent sodium currents and repetitive firing in rat spinal motoneurons
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DOI：
10.1152/jn.00341.2006
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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.
脊髓和脊髓运动神经元由血清素 (5-HT) 和去甲肾上腺素 (NE) 神经元末端密集支配，这些神经元主要来自脑干，但也来自内在的脊髓神经元。即使在长期脊柱横断（慢性脊柱）后，大量（10%）的 5-HT 和 NE（单胺）仍残留在损伤尾部。为了确定这种内源性单胺的作用，我们用单胺受体拮抗剂阻断它们的作用，并测量钠电流和运动神经元放电的变化。我们重点关注持续钠电流 (Na PIC) 和钠尖峰特性，因为它们对于运动神经元重复放电至关重要，并且由单胺促进。细胞内记录是从正常和慢性脊髓大鼠的骶尾脊髓的运动神经元（2个月骶后横断）中进行的，整个骶尾索被急性切除并在体外保存（来自正常大鼠的脊髓称为急性脊髓）。急性和慢性脊髓大鼠的 TTX 敏感 Na PIC 分别为 0.62 +/- 0.76 和 1.60 +/- 1.04 nA，平均起始电压为 -63.0 +/- 5.6 和 -64.1 +/- 5.4 mV（用缓慢电压斜坡测量）。在急性和慢性脊髓大鼠中，使用 5-HT2A、5-HT2C 和 α1-NE 受体拮抗剂（分别为酮色林、RS 102221 和 WB 4101）可显着降低 Na PIC，而联合应用这三种单胺拮抗剂可完全消除 Na PIC。同样，长期施用镉可减少突触前递质释放（包括 5-HT 和 NE），也消除了 Na PIC。与单胺拮抗剂中 Na PIC 的消除相关，运动神经元在缓慢的电流斜坡期间失去了放电能力。此时，逆向刺激引起的尖峰不受影响，表明瞬时钠电流的激活没有受到损害。然而，缓慢斜坡去极化后引起的尖峰在高度和上升速率上略有降低，表明由于通道失活增加而导致钠通道可用性降低。这些结果表明，内源性单胺受体激活对于启用 Na PIC 和减少钠通道失活至关重要，最终使正常和慢性脊髓大鼠能够稳定地重复放电。
The spinal cord and spinal motoneurons are densely innervated by terminals of serotonin (5-HT) and norepinephrine (NE) neurons arising mostly from the brain stem, but also from intrinsic spinal neurons. Even after long-term spinal transection (chronic spinal), significant amounts (10%) of 5-HT and NE (monoamines) remain caudal to the injury. To determine the role of such endogenous monoamines, we blocked their action with monoamine receptor antagonists and measured changes in the sodium currents and firing in motoneurons. We focused on persistent sodium currents (Na PIC) and sodium spike properties because they are critical for enabling repetitive firing in motoneurons and are facilitated by monoamines. Intracellular recordings were made from motoneurons in the sacrocaudal spinal cord of normal and chronic spinal rats (2 mo postsacral transection) with the whole sacrocaudal cord acutely removed and maintained in vitro (cords from normal rats termed acute spinal). Acute and chronic spinal rats had TTX-sensitive Na PICs that were respectively 0.62 +/- 0.76 and 1.60 +/- 1.04 nA, with mean onset voltages of -63.0 +/- 5.6 and -64.1 +/- 5.4 mV, measured with slow voltage ramps. Application of 5-HT2A, 5-HT2C, and alpha 1-NE receptor antagonists (ketanserin, RS 102221, and WB 4101, respectively) significantly reduced the Na PICs, and a combined application of these three monoamine antagonists completely eliminated the Na PIC, in both acute and chronic spinal rats. Likewise, reduction of presynaptic transmitter release (including 5-HT and NE) with long-term application of cadmium also eliminated the Na PIC. Associated with the elimination of the Na PIC in monoamine antagonists, the motoneurons lost their ability to fire during slow current ramps. At this point, the spike evoked by antidromic stimulation was not affected, suggesting that activation of the transient sodium current was not impaired. However, the spike evoked after a slow ramp depolarization was slightly reduced in height and rate-of-rise, suggesting decreased sodium channel availability as a result of increased channel inactivation. These results suggest that endogenous monoamine receptor activation is critical for enabling the Na PIC and decreasing sodium channel inactivation, ultimately enabling steady repetitive firing in both normal and chronic spinal rats.