Osaka University Graduate School of Medicine, Department of Anesthesiology & Intensive Care, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Neurosci Lett. 2013 Jan 4;532:49-54. doi: 10.1016/j.neulet.2012.10.034. Epub 2012 Nov 2.
Spinal cord injury can have debilitating consequences, commonly resulting in motor dysfunction below the lesion site and the development of chronic pain syndromes. The serotonin pathway is important for inhibiting noxious stimuli and facilitating motor function after spinal cord injury. The serotonin 2C receptor (5HTR2C) has several characteristic features, and is regulated by the amount of serotonin 2C receptor as well as RNA editing and alternative splicing. In this study, we used a rat model of spinal contusion injury to investigate the relationship between the pain threshold and 5HTR2C alternative splicing. The pain threshold was assessed using mechanical stimulation with von Frey filaments. We then used real-time PCR to examine the RNA levels of 5HTR2C in three sections of the spinal cord: the rostral, injury-core, and caudal positions. On postoperative day 12, the pain threshold in injured rats was significantly reduced compared with sham-operated and naïve rats. The total 5HTR2C levels were significantly lower in injured rats than in naïve rats at all positions, and significantly lower in injured rats compared with sham-operated rats at injury-core and caudal positions. The ratio of exon Vb-skipped nonfunctional 5HTR2C mRNA to total 5HTR2C was significantly higher in injured rats compared with naïve rats at the injury-core and caudal positions, and significantly higher in injured rats compared with sham-operated rats at the caudal position. These results indicate that spinal contusion injury, which causes neuropathic pain, induces serotonergic dysfunction. This dysfunction appears to be mediated by decreased 5HTR2C mRNA expression, and alternative splicing. These results confirm the importance of considering splice variants when examining 5HTR2C.
脊髓损伤会导致严重的后果，通常会导致损伤部位以下的运动功能障碍和慢性疼痛综合征的发展。5-羟色胺能通路对于抑制有害刺激和促进脊髓损伤后的运动功能很重要。5-羟色胺 2C 受体（5HTR2C）具有几个特征，其表达受到 5HTR2C 受体数量、RNA 编辑和选择性剪接的调节。在本研究中，我们使用大鼠脊髓挫伤损伤模型来研究疼痛阈值与 5HTR2C 选择性剪接之间的关系。采用 von Frey 纤维机械刺激评估疼痛阈值。然后，我们使用实时 PCR 检测脊髓三个节段（损伤前、损伤核心和损伤后）的 5HTR2C RNA 水平。术后第 12 天，与假手术和未损伤组相比，损伤组大鼠的疼痛阈值明显降低。与未损伤组相比，所有部位损伤组大鼠的总 5HTR2C 水平明显降低，损伤核心和损伤后部位的总 5HTR2C 水平明显低于假手术组大鼠。与未损伤组相比，损伤核心和损伤后部位的外显子 Vb-跳跃非功能 5HTR2C mRNA 与总 5HTR2C 的比值在损伤组大鼠中明显升高，在损伤后部位与假手术组大鼠相比也明显升高。这些结果表明，导致神经性疼痛的脊髓挫伤损伤会引起 5-羟色胺能功能障碍。这种功能障碍似乎是由 5HTR2C mRNA 表达减少和选择性剪接引起的。这些结果证实了在研究 5HTR2C 时考虑剪接变体的重要性。
