褪黑素通过降低 Na1.8 表达和伤害性神经元敏化来减轻慢性内脏痛。
Melatonin attenuated chronic visceral pain by reducing Na1.8 expression and nociceptive neuronal sensitization.
机构信息
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou, P.R. China.
Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, P. R. China.
出版信息
Mol Pain. 2023 Jan-Dec;19:17448069231170072. doi: 10.1177/17448069231170072.
BACKGROUND
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder, and its specific pathogenesis is still unclear. We have previously reported that TTX-resistant (TTX-R) sodium channels in colon-specific dorsal root ganglion (DRG) neurons were sensitized in a rat model of visceral hypersensitivity induced by neonatal colonic inflammation (NCI). However, the detailed molecular mechanism for activation of sodium channels remains unknown. This study was designed to examine roles for melatonin (MT) in sensitization of sodium channels in NCI rats.
METHODS
Colorectal distention (CRD) in adult male rats as a measure of visceral hypersensitivity. Colon-specific dorsal root ganglion (DRG) neurons were labeled with DiI and acutely dissociated for measuring excitability and sodium channel current under whole-cell patch clamp configurations. Western blot and Immunofluorescence were employed to detect changes in expression of Na1.8 and MT2.
RESULTS
The results showed that rats exhibited visceral hypersensitivity after NCI treatment. Intrathecal application of melatonin significantly increased the threshold of CRD in NCI rats with a dose-dependent manner, but has no role in the control group. Whole-cell patch clamp recording showed that melatonin remarkably decreased the excitability and the density of TTX-R sodium channel in DRG neurons from NCI rats. The expression of MT2 receptor at the protein level was markedly lower in NCI rats. 8MP, an agonist of MT2 receptor, enhanced the distention threshold in NCI rats. Application of 8MP reversed the enhanced hypersensitivity of DRG neurons from NCI rats. 8MP also reduced TTX-R sodium current density and modulated dynamics of TTX-R sodium current activation.
CONCLUSIONS
These data suggest that sensitization of sodium channels of colon DRG neurons in NCI rats is most likely mediated by MT2 receptor, thus identifying a potential target for treatment for chronic visceral pain in patients with IBS.
背景
肠易激综合征（IBS）是一种常见的功能性胃肠道疾病，其特定的发病机制仍不清楚。我们之前报道过，在由新生儿结肠炎症（NCI）诱导的内脏高敏性大鼠模型中，结肠特异性背根神经节（DRG）神经元中的TTX 抗性（TTX-R）钠通道被敏化。然而，钠通道激活的详细分子机制仍不清楚。本研究旨在探讨褪黑素（MT）在 NCI 大鼠钠通道敏化中的作用。
方法
成年雄性大鼠的结肠扩张（CRD）作为内脏高敏性的测量指标。用 DiI 标记结肠特异性背根神经节（DRG）神经元，并用全细胞膜片钳构型急性分离以测量兴奋性和钠通道电流。Western blot 和免疫荧光用于检测 Na1.8 和 MT2 表达的变化。
结果
结果显示，NCI 处理后大鼠表现出内脏高敏性。鞘内给予褪黑素可显著增加 NCI 大鼠 CRD 的阈值，呈剂量依赖性，但对对照组无作用。全细胞膜片钳记录显示，褪黑素可显著降低 NCI 大鼠 DRG 神经元的兴奋性和 TTX-R 钠通道的密度。MT2 受体的蛋白水平在 NCI 大鼠中明显降低。MT2 受体激动剂 8MP 可增强 NCI 大鼠的扩张阈值。8MP 的应用逆转了 NCI 大鼠 DRG 神经元的超敏反应。8MP 还降低了 TTX-R 钠电流密度，并调节了 TTX-R 钠电流激活的动力学。
结论
这些数据表明，NCI 大鼠结肠 DRG 神经元钠通道的敏化很可能是由 MT2 受体介导的，从而为 IBS 患者慢性内脏疼痛的治疗提供了一个潜在的靶点。
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