TLR调节背根神经节TRPV1在慢性胰腺炎疼痛中的作用机制研究

Pain is the most troublesome symptom of chronic pancreatitis (CP), and the mechanism of pain in CP is not fully understood, therefore there is no completely satisfactory treatment option. In recent years, neurological inflammation is considered to be a possible mechanism of pain in CP. Our previous study suggested proteinase-activated receptor 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) was significantly up-regulated in dorsal root ganglia (DRGs) in rats with CP, and PAR2 activation could convey nociceptive messages directly or sensitize TRPV1 receptor indirectly, which leads to the development of visceral hyperalgesia and neurogenic inflammation. Evidence suggests TLRs play a vital role in the neuron injury of periphery and central nervous system, however, little is known in the role of TLRs in the pain of CP. In present study, we will use the trinitro-benzene-sulfonic acid (TNBS) retrograde injection into pancreatic and biliary model to induce CP, and through electroneurophysiology and molecular biology, as well as morphology methods, we aim to determine if the increased expression of Hot Shock Proteins (HSPs) can activate the TLRs, and whether activated TLRs will up-regulate the expression of TRPV1 in pancreatic tissue and DRGs to mediate the development and maintain of nociception. The effects of blocking HSPs-TLRs-TRPV1 pathway on the pain and inflammation of CP will be investigated. Overall the present study will focus on the role of TLRs in the pathogenesis of pain of CP, show insights for the understanding of pain of CP, and provide target for future treatment.

疼痛是慢性胰腺炎(CP)最主要的症状，其发病机制尚未被完全阐明，因此目前尚无满意的治疗手段。研究表明神经源性炎症很可能是慢性胰腺炎疼痛的主要病因。我们既往研究证实蛋白酶激活受体2(PAR2)和辣椒素(TRPV1)在CP大鼠的背根神经节(DRG)中表达明显上调；PAR2可能通过致敏TRPV1受体介导CP痛觉高敏的形成。目前研究提示TLRs在外周神经系统和中枢神经系统的神经损伤中发挥作用，但TLRs在慢性胰腺炎疼痛中的研究极少，作用尚未阐明。在本研究中我们拟采用三硝基苯磺酸(TNBS)逆行胰胆管注射的方法建立CP大鼠模型，通过神经电生理结合分子生物学和形态学方法，明确胰腺组织热休克蛋白(HSPs)表达增加是否可激活TLRs，验证TLRs激活后是否增加胰腺组织局部及DRG 的TRPV1表达介导疼痛的形成和维持，探索阻断HSPs-TLRs-TRPV1途径对CP的疼痛和炎症分别发挥何种作用。

疼痛是慢性胰腺炎(CP)最主要的症状，其发病机制尚未被完全阐明，因此目前尚无满意的治疗手段。研究表明神经源性炎症很可能是慢性胰腺炎疼痛的主要病因。我们既往研究证实蛋白酶激活受体2(PAR2)和辣椒素(TRPV1)在CP 大鼠的背根神经节(DRG)中表达明显上调；PAR2 可能通过致敏TRPV1 受体介导CP 痛觉高敏的形成。目前研究提示TLRs 在外周神经系统和中枢神经系统的神经损伤中发挥作用，但TLRs 在慢性胰腺炎疼痛中的研究极少，作用尚未阐明。在本研究中我们拟采用三硝基苯磺酸(TNBS)逆行胰胆管注射的方法建立CP大鼠模型，发现对应节段背根神经节内TLRs表达变化，其中TLR9表达显著升高，而TLR3和TLR7表达无显著变化。同时鞘内注射TLR9特异性拮抗剂OND2088 可抑制由慢性胰腺炎造成的腹部热痛阈降低的现象。提示TLR9升高是介导慢性胰腺炎疼痛的可能机制。