Department of Anatomy & Neurobiology, University of Vermont, Burlington, VT 05405, USA.
Neurogastroenterol Motil. 2011 Jul;23(7):673-e279. doi: 10.1111/j.1365-2982.2011.01702.x. Epub 2011 Mar 23.
Colitis is associated with increased excitability of afterhyperpolarization neurons (AH neurons) and facilitated synaptic transmission in the myenteric plexus. These changes are accompanied by disrupted propulsive motility, particularly in ulcerated regions. This study examined the relationship between myenteric AH neuronal hyperexcitability and disrupted propulsive motility.
The voltage-activated Na(+) channel opener veratridine, the intermediate conductance Ca(2+) -activated K(+) channel inhibitor TRAM-34 and the 5-HT(4) receptor agonist tegaserod were used to evaluate the effects of neuronal hyperexcitability and synaptic facilitation on propulsive motility in normal guinea pig distal colon. Because trinitrobenzene sulfonic acid (TNBS)-colitis-induced hyperexcitability of myenteric afferent neurons involves increases in hyperpolarization-activated, cyclic nucleotide-gated (HCN) channel activity, the HCN channel inhibitors Cs(+) and ZD7288 were used to suppress AH neuronal activity in TNBS-colitis.
In non-inflamed preparations, veratridine halted propulsive motility (P<0.001). The rate of propulsive motor activity was significantly reduced following addition of TRAM-34 and tegaserod (P<0.001). In TNBS-inflamed preparations, in which motility was temporarily halted or obstructed at sites of ulceration, both Cs(+) and ZD7288 normalized motility through the inflamed regions. Immunohistochemistry studies demonstrated that the proportion of AH neurons in the myenteric plexus was unchanged in ulcerated regions, but there was a 10% reduction in total number of neurons per ganglion.
These findings support the concept that inflammation-induced neuroplasticity in myenteric neurons, involving changes in ion channel activity that lead to enhanced AH neuronal excitability, can contribute to impaired propulsive colonic motility.
结肠炎与节后超极化神经元（AH 神经元）的兴奋性增加和肌间神经丛中的突触传递增强有关。这些变化伴随着推进运动的紊乱，特别是在溃疡性区域。本研究检查了肌间 AH 神经元过度兴奋与推进运动紊乱之间的关系。
使用电压激活的钠离子通道 opener 藜芦碱、中间电导钙激活的钾通道抑制剂 TRAM-34 和 5-HT4 受体激动剂替加色罗来评估神经元过度兴奋和突触易化对正常豚鼠远端结肠推进运动的影响。由于三硝基苯磺酸（TNBS）-结肠炎诱导的肌间传入神经元的过度兴奋涉及超极化激活、环核苷酸门控（HCN）通道活性的增加，因此使用 HCN 通道抑制剂 Cs+和 ZD7288 来抑制 TNBS-结肠炎中的 AH 神经元活性。
在非炎症性制剂中，藜芦碱停止了推进运动（P<0.001）。添加 TRAM-34 和替加色罗后，推进运动活动的速度显著降低（P<0.001）。在 TNBS 炎症性制剂中，运动在溃疡部位暂时停止或受阻，Cs+和 ZD7288 均可使炎症区域的运动正常化。免疫组织化学研究表明，溃疡性区域肌间神经丛中的 AH 神经元比例不变，但每个神经节中的神经元总数减少了 10%。
这些发现支持这样一种概念，即肌间神经元的炎症诱导的神经可塑性，涉及改变离子通道活性，导致 AH 神经元兴奋性增强，可能导致推进性结肠运动障碍。
