姜黄素以炎症-TRPV1为靶点治疗内脏痛的机制研究

Visceral pain is the most common symptom in clinic.It is difficult to cure patients with visceral pain. Previous studies indicate that inflammation and upregulation of transient receptor potential vanilloid 1 (TRPV1) expression and function on the visceral nociceptors contribute to visceral hyperalgesia. Curcumin has anti-cancer, anti-inflammatory and anti-oxidant activities. Our preliminary data showed that 1) curcumin attentuated colorectal distention (CRD)-induced viscero-motor response (VMR) in visceral pain model in rats; 2) the capsaicin-induced TRPV1 activation was decreased by curcumin.Thus, we hypothesized that curcumin which has multiple activities such as anti-inflammation and TRPV1 antagonism may play a therapeutic effect for visceral pain via inhibiting inflammation-TRPV1 positive feedback.In the present project, we will utilize multidisciplinary approach to investigate 1) the anti-inflammation and anti-nociception induced by curcumin in visceral pain; 2) the effects of curcumin on TRPV1 activation induced by different stimuli including capsaicin, H+ and heat; 3) the efficacy of curcumin-induced TRPV1 antagonism following phosphorylation and glycosylation of TRPV1.These will elucidate the potential therapeutic action of ccurcumin for visceral pain and its molecular mechanisms.

内脏痛是临床上最常见的症状，其治疗也是临床难题。既往研究表明炎症和内脏伤害性感受器TRPV1表达和功能上调是内脏痛敏的重要原因。姜黄素具有抗肿瘤、抗炎和抗氧化等作用，而我们的前期工作发现：1）在内脏痛动物模型，姜黄素能抑制扩张结直肠引起的内脏运动反应；2）姜黄素拮抗辣椒素对TRPV1的激活。我们推测，兼有抗炎和拮抗TRPV1通道等多重效应的姜黄素可能打破炎症-TRPV1间的正反馈循环从而有效治疗内脏痛。本项目拟采用多种实验方法，观察姜黄素的抗炎作用及镇痛效应，研究姜黄素对辣椒素、热刺激和H+诱发的TRPV1通道活动的影响，探讨姜黄素对磷酸化和糖基化修饰的TRPV1通道的拮抗效应。通过以上研究，确定姜黄素在内脏痛治疗中的潜在价值，在细胞分子水平揭示其作用机制。

内脏痛是临床上最常见的症状，其治疗也是临床难题。既往研究表明炎症和内脏伤害性感受器TRPV1表达和功能上调是内脏痛敏的重要原因。姜黄素具有抗肿瘤、抗炎和抗氧化等作用，而我们的前期工作发现TRPV1可能是姜黄素治疗内脏痛的靶点。通过本项目的深入研究，我们证明了姜黄素减轻内脏伤害性感受作用可能是通过抑制TRPV1功能实现的；另外，我们利用溃疡性结肠炎模型大鼠证明了姜黄素具有预防和治疗内脏痛的效应，也能够预防炎症反应，其镇痛效应可能与抑制TRPV1磷酸化有关，再者，在细胞水平我们证明了姜黄素抑制TRPV1磷酸化从而阻断TRPV1的上膜。这些研究表明姜黄素具有抗炎和镇痛效应，可能是通过抑制TRPV1磷酸化，进而抑制TRPV1上膜和TRPV1功能实现的。本课题确证了姜黄素对内脏痛的治疗效应，并揭示了其分子作用机制，这将为姜黄素在内脏痛治疗中的应用提供实验依据，具有临床应用指导价值。